Clinical trial NCT03607838
Conditions: Lumbar Disc Herniation
Keywords: Lumbar disc herniation Radiculopathy Sciatica Intradiscal injection Chemonucleolysis
Sponsor: Seikagaku Corporation
Start date: 2018-11-07; Completion date: 2023-03-21
Enrollment: 352 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study is to evaluate the effectiveness of a single-dose intervertebral disc injection of SI-6603 in subjects with lumbar disc herniation (LDH)

Detailed description:

Arms: arm 1: Condoliase: 1.25U, intradiscal injection, one time

For patients in the active treatment group, a volume of 1.0 mL was administered into the intervertebral disc in a single dose. arm 2: Sham injection

For patients in the control group, a solution was not prepared and the needle was not placed in the intervertebral disc.
Interventions: intervention 1: SI-6603 intervention 2: Sham injection
Intervention descriptions: intervention 1: SI-6603 will be injected into an intervertebral disc. intervention 2: The injection will be performed without needle placement into an intervertebral disc.

Protocol documents:
Prot_000.pdf: 
Protocol Number 6603/1133  
Sponsor: Seikagaku Corporation 
Clinical Study Protocol: 
 
 
 
 
 
 
 
 
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Clinical Study Protocol 
Protocol Title: 
A Multicenter, Randomized, Double-blind, Sham-
controlled, Comparative Study of SI-6603 in Subjects with 
Lumbar Disc Herniation (Phase 3)
Protocol Number: 
6603/1133 
Study Phase: 
Phase 3 
Investigational Product: 
SI-6603 
IND Number: 
100,398 
Sponsor: 
Seikagaku Corporation 
6-1, Marunouchi 1-chome 
Chiyoda-ku, Tokyo 100-0005, Japan 
Date of Protocol: 
14, February 2020 
Version Number: 
7.0
This document contains confidential information of Seikagaku Corporation. 
Do not copy or distribute without written permission from the sponsor. 
CONFIDENTIAL
 
 
NCT number:
NCT03607838


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LIST OF STUDY PERSONNEL 
Sponsor
Yosuke Funakoshi
Executive Vice President, Clinical Development 
Department 
Research and Development Division 
Seikagaku Corporation 
Kyoichi Osano
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 
Safety Physician/ 
Emergency Contact 
 
 


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SIGNATURE PAGE 
 
Declaration of Sponsor  
Title: A Multicenter, Randomized, Double-blind, Sham-controlled, Comparative Study 
of SI-6603 in Subjects with Lumbar Disc Herniation (Phase 3) 
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 (SI-6603 or 
control [sham injection]), as well as with the moral, ethical, and scientific principles 
governing clinical research as set out in the Declaration of Helsinki, and the guidelines on 
Good Clinical Practice. 
 
 
_____________________________________ 
_____________________ 
Yosuke Funakoshi 
 
 
 
Date 
Executive Vice President, Clinical Development Department 
Research and Development Division 
Seikagaku Corporation 
 
 


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Declaration of the Principal Investigator  
Title: A Multicenter, Randomized, Double-blind, Sham-controlled, Comparative Study 
of SI-6603 in Subjects 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. Documentation includes this study protocol, 
investigator's brochure, case report form, and other scientific documents or data. 
The study will not commence without the prior written approval of a properly constituted 
Institutional Review Board (IRB). No changes will be made to the study protocol without the 
prior written approval of the Sponsor and the IRB, except where necessary to eliminate an 
immediate hazard to the subjects. 
I have read, understood, and agree to abide by all the conditions and instructions contained in 
this protocol. 
 
Principal Investigator  
 
 
 
_____________________________________ 
_____________________ 
Signature 
Date 
 
_____________________________________ 
Name (block letters) 
 
_____________________________________ 
Title (block letters) 
 
_____________________________________ 
Institution (block letters) 
 
_____________________________________ 
Phone number 


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SYNOPSIS 
Protocol Title: 
A Multicenter, Randomized, Double-blind, Sham-controlled, 
Comparative Study of SI-6603 in Subjects with Lumbar Disc 
Herniation (Phase 3) 
Protocol Number: 
6603/1133 
Investigational Product: 
SI-6603 
Study Phase: 
Phase 3 
Objectives 
Primary Objective: 
The primary objective is to evaluate the effectiveness of a 
single-dose intervertebral disc injection of SI-6603 at a dose of 
1.25 units (U) compared to control in subjects with lumbar disc 
herniation (LDH) by comparing the change in worst leg pain 
during the past 24 hours, as assessed by visual analogue scale 
(VAS), from baseline to Week 13 after injection of the 
investigational product. 
Secondary Objectives: 
The secondary objectives are to evaluate the efficacy of SI-6603 
1.25 U for key secondary endpoints, and to demonstrate whether 
SI-6603 1.25 U is safe and well tolerated. 
Overall Study Design 
Study Design: 
This is a multicenter, randomized, double-blind, sham-
controlled, comparative study. The study duration for each 
subject will be approximately 56 weeks: a 4-week screening 
period, a 1-day treatment administration day, and a 52-week 
follow-up period.  
Dosage/Dose Regimen: 
Subjects randomized to the SI-6603 treatment group will 
receive a single-dose injection of SI-6603 1.25 U into an 
intervertebral disc. Subjects randomized to the control group 
will receive a sham injection (the needle will not be placed in 
the disc). 
Duration of Treatment: 
Single injection 
Planned Number of 
Subjects:  
It is planned to enroll approximately 320 subjects, 160 in the SI-
6603 group and 160 in the control group. 


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Study Population 
Summary:  
The study population will consist of male and female subjects, 
30 to 70 years of age (inclusive) at the time of informed 
consent, with single-level LDH (L4-L5 or L5-S1 (or L5-L6)) 
with clear, demonstrable nerve root impingement as assessed by 
magnetic resonance imaging (MRI) and clinical symptoms 
corresponding to position of the impaired nerve root. 
Criteria for Evaluation 
Efficacy Assessments:  
Primary: 
The primary endpoint is the change from baseline to Week 13 in 
average worst leg pain score during the past 24 hours over the 
previous 7 days, as assessed by 100 mm VAS. 
Key Secondary: 
The key secondary endpoints include the following: 
1) Change from baseline to Week 13 in herniation volume 
2) Change from baseline to Week 13 in Oswestry Disability 
Index (ODI) score 
3) Change from baseline to Week 52 in average worst leg 
pain score during the past 24 hours over the previous 7 
days, as assessed by 100 mm VAS. 
Secondary: 
Additional secondary endpoints are described in the full 
protocol. 
Safety Assessments: 
The following safety endpoints will be assessed after 
investigational product administration: 
 
Adverse events  
 
Laboratory tests 
 
Vital signs 
 
Imaging assessment by X-ray and MRI 
- 
Disc height (disc index) 
- 
Vertebral body translation 
- 
Vertebral body angle formed by flexion 


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- 
Modic classification 
 
Occurrence of post-treatment lumbar surgery 
- 
Surgery for treatment of LDH at a different 
level than administration of the investigational 
product 
- 
Lumbar surgery not for treatment of LDH  
Statistical Methods: 
The change from baseline in the worst leg pain scores will be 
analyzed by a mixed model for repeated measures (MMRM) 
analysis for Week 1 through Week 52 in the modified intention-
to-treat (mITT) population. The average worst leg pain scores 
over the previous 7 days will be analyzed at Week 1, 2, 4, 6, 13, 
26, 39, 52. The primary comparison will be the mean change 
from baseline of the SI-6603 group at Week 13 compared with 
the control group, estimated using this model. The model will 
include the baseline worst leg pain score, treatment, time, 
treatment-by-time interaction, and duration of leg pain as fixed 
effects. An unstructured covariance will be used to model the 
covariance structure among repeated measures. Should the model 
fail to converge with the type = UN option, a compound 
symmetry structure will be used. Kenward-Roger method will be 
used for computing the denominator degrees of freedom. The 
missing data will be implicitly handled via a mixed-effect model, 
without explicit imputation. 
Statistical methods for key secondary endpoints and adjustment 
for multiplicity are described in the full protocol. 
 
 
 


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TABLE OF CONTENTS  
1 
INTRODUCTION ....................................................................................................... 15 
1.1 
Background ............................................................................................................ 15 
1.1.1 
Summary of Clinically Significant Findings Obtained in Nonclinical Studies 
and Clinical Studies ........................................................................................... 16 
1.1.2 
Current Study .................................................................................................... 16 
1.2 
Risk and Benefit ..................................................................................................... 16 
1.2.1 
Possible Risks ................................................................................................... 16 
1.2.2 
Possible Benefits ............................................................................................... 18 
1.2.3 
Rationale for Study Design, Administration Route, Dosage (Regimen), and 
Treatment Period Selection ................................................................................ 19 
2 
OBJECTIVES .............................................................................................................. 20 
2.1 
Primary Objective ................................................................................................... 20 
2.2 
Secondary Objectives ............................................................................................. 20 
3 
STUDY DESIGN AND PLAN .................................................................................... 21 
3.1 
Study Design .......................................................................................................... 21 
3.2 
Dosage/Dose Regimen ............................................................................................ 21 
3.3 
Study Population .................................................................................................... 21 
3.4 
Duration of Study ................................................................................................... 21 
3.5 
Study Assessments ................................................................................................. 21 
3.6 
Planned Number of Subjects ................................................................................... 21 
3.7 
Randomization ....................................................................................................... 22 
3.8 
Study Design Schematic ......................................................................................... 22 
4 
STUDY POPULATION .............................................................................................. 23 
4.1 
Inclusion Criteria .................................................................................................... 23 
4.2 
Exclusion Criteria ................................................................................................... 24 
5 
SUBJECT WITHDRAWAL FROM THE STUDY ...................................................... 30 
5.1 
Criteria for Subject Withdrawal .............................................................................. 30 
5.2 
Procedures for Subject Withdrawal ......................................................................... 31 
5.3 
Post-treatment Surgery Follow-up for Withdrawn Subjects ..................................... 31 
6 
STUDY METHOD AND PROCEDURES ................................................................... 32 
6.1 
Informed Consent ................................................................................................... 32 
6.1.1 
Subject Identification ........................................................................................ 33 
6.2 
Screening................................................................................................................ 33 


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6.2.1 
Central Imaging Eligibility Assessment ............................................................. 33 
6.2.2 
Handling of Concomitant Medications .............................................................. 33 
6.2.3 
Subject Daily Diary ........................................................................................... 33 
6.2.4 
Re-screening ..................................................................................................... 33 
6.3 
Subject Study Entry ................................................................................................ 34 
6.3.1 
Allocation/Randomization of Subjects to Treatment .......................................... 35 
6.4 
Investigational Product or Sham Injection Procedure .............................................. 35 
6.5 
Treatment Blinding ................................................................................................. 35 
6.6 
Concomitant Medications ....................................................................................... 36 
6.6.1 
Prohibited Medications ...................................................................................... 36 
6.6.2 
Restricted Concomitant Medications ................................................................. 36 
6.6.3 
Medication Use Before, After or During the Injection Procedure ....................... 37 
6.6.4 
Rescue Medications ........................................................................................... 37 
6.7 
Concomitant Therapies ........................................................................................... 38 
6.7.1 
Prohibited Concomitant Therapies ..................................................................... 38 
6.7.2 
Restricted Concomitant Therapies ..................................................................... 39 
6.7.3 
Lifestyle Restrictions ......................................................................................... 39 
7 
INVESTIGATIONAL PRODUCT ............................................................................... 39 
7.1 
Identity of Investigational Products......................................................................... 39 
7.1.1 
SI-6603 ............................................................................................................. 39 
7.1.2 
Control .............................................................................................................. 39 
7.2 
Packaging and Labeling .......................................................................................... 40 
7.3 
Preparation, Handling, Storage, and Accountability ................................................ 40 
8 
ENDPOINTS ............................................................................................................... 41 
8.1 
Efficacy Endpoints ................................................................................................. 41 
8.1.1 
Primary ............................................................................................................. 41 
8.1.2 
Key Secondary .................................................................................................. 41 
8.1.3 
Other Secondary ................................................................................................ 41 
8.2 
Safety Endpoints..................................................................................................... 43 
9 
STUDY SCHEDULE AND VARIABLES ................................................................... 44 
9.1 
Schedule of Activities ............................................................................................. 44 
9.2 
Procedures by Visit ................................................................................................. 46 
9.2.1 
Visit 1: Screening Period (Day -28 to Day -1) ................................................... 46 
9.2.2 
Visit 2: Randomization (Day -1 or Day 1) ......................................................... 47 
9.2.3 
Visit 2: Investigational Product Treatment (Day 1) ............................................ 48 
9.2.4 
Visit 3: Week 1 (Day 8 ±1 day) ......................................................................... 49 


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9.2.5 
Visits 4 and 5: Week 2 (Day 15 ±3 days) and Week 4 (Day 29 ±3 days) ............ 49 
9.2.6 
Visit 6: Week 6 (Day 43 ±7 days) ...................................................................... 50 
9.2.7 
Visit 7: Week 13 (Day 92 -7, +14 days) ............................................................. 51 
9.2.8 
Visit 8: Week 26 (Day 183 ±14 days) ................................................................ 51 
9.2.9 
Visit 9: Week 39 (Day 274 ±14 days) ................................................................ 52 
9.2.10 Visit 10: Week 52 (Day 365 ±14 days) .............................................................. 52 
9.2.11 Discontinuation Visit ......................................................................................... 53 
9.2.12 Unscheduled Visit ............................................................................................. 54 
9.3 
Background and Demographic Characteristics ........................................................ 54 
9.3.1 
Demographics ................................................................................................... 54 
9.3.2 
History of Lumbar Disc Herniation ................................................................... 54 
9.3.3 
Medical History................................................................................................. 55 
9.4 
Concomitant Medications/Therapies ....................................................................... 55 
9.4.1 
Concomitant Medications .................................................................................. 55 
9.4.2 
Concomitant Therapies ...................................................................................... 55 
9.5 
Efficacy Assessments ............................................................................................. 56 
9.5.1 
Pain Intensity .................................................................................................... 56 
9.5.2 
Oswestry Disability Index ................................................................................. 56 
9.5.3 
36-item Short Form Survey ............................................................................... 56 
9.5.4 
EuroQol Group 5-Dimension Quality of Life Instrument ................................... 56 
9.5.5 
Patient Global Impression of Change ................................................................. 56 
9.5.6 
Clinical Global Impression of Change ............................................................... 57 
9.5.7 
Work Productivity and Activity Impairment ...................................................... 57 
9.5.8 
Rescue Medication Use ..................................................................................... 57 
9.5.9 
Neurologic Status .............................................................................................. 57 
9.5.10 Treatment Failure .............................................................................................. 57 
9.5.11 Disc and Herniation Volumes ............................................................................ 58 
9.5.12 Post-treatment Surgery for Lumbar Disc Herniation at Target Level .................. 58 
9.6 
Safety Assessments ................................................................................................ 58 
9.6.1 
Adverse Events ................................................................................................. 58 
9.6.2 
Laboratory Tests ............................................................................................... 59 
9.6.3 
Vital Signs ........................................................................................................ 61 
9.6.4 
Assessments by X-ray and MR Images .............................................................. 61 
9.6.5 
Post-treatment Surgery for LDH at Non-target Level ......................................... 61 
9.6.6 
Post-treatment Lumbar Surgery Not for LDH .................................................... 61 
9.7 
Other Assessments.................................................................................................. 62 


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9.7.1 
Pregnancy Test .................................................................................................. 62 
9.8 
Subject Education ................................................................................................... 62 
9.8.1 
Accurate Pain Reporting Training ..................................................................... 62 
9.8.2 
Appropriate Expectations Training .................................................................... 62 
10 ADVERSE EVENTS ................................................................................................... 63 
10.1 Definitions .............................................................................................................. 63 
10.1.1 Adverse Events ................................................................................................. 63 
10.1.2 Serious Adverse Events ..................................................................................... 64 
10.1.3 Vital Signs and Laboratory Tests ....................................................................... 65 
10.1.4 Anaphylaxis ...................................................................................................... 65 
10.1.5 Adverse Events of Special Interest .................................................................... 65 
10.2 Assessment of Adverse Events ............................................................................... 66 
10.2.1 Intensity ............................................................................................................ 66 
10.2.2 Causality ........................................................................................................... 67 
10.3 Follow-up of Adverse Events.................................................................................. 67 
10.4 Reporting Serious Adverse Events .......................................................................... 67 
10.5 Action Taken for Adverse Events ........................................................................... 68 
10.6 Action Taken for Serious Adverse Events ............................................................... 68 
11 STATISICAL METHODS ........................................................................................... 68 
11.1 Analysis Populations .............................................................................................. 68 
11.2 Modified Intention-to-Treat Population .................................................................. 68 
11.3 Per Protocol Population .......................................................................................... 69 
11.4 Safety Population ................................................................................................... 69 
11.5 Demographics, Baseline Characteristics, Medical History, and Concomitant 
Medications ............................................................................................................ 69 
11.6 Efficacy Analyses ................................................................................................... 69 
11.6.1 Primary ............................................................................................................. 69 
11.6.2 Key Secondary .................................................................................................. 69 
11.6.3 Other Secondary ................................................................................................ 70 
11.7 Safety Analyses ...................................................................................................... 71 
11.8 General Considerations ........................................................................................... 71 
11.8.1 Data Handling of Worst Leg Pain ...................................................................... 71 
11.8.2 Visit Window and Unscheduled Assessments .................................................... 72 
11.8.3 Significance Level and Confidence Coefficient ................................................. 72 
11.8.4 Missing Data ..................................................................................................... 72 
11.8.5 Adjustment for Multiplicity ............................................................................... 72 


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11.8.6 Sample Size Determination ............................................................................... 73 
12 ETHICAL CONSIDERATION .................................................................................... 73 
12.1 Good Clinical Practice Compliance ........................................................................ 73 
12.2 Institutional Review Board or Independent Ethics Committee Approval ................. 73 
12.3 Data Protection ....................................................................................................... 74 
12.4 Premature Termination of the Study ....................................................................... 74 
13 PROTOCOL ADHERENCE AND INVESTIGATOR AGREEMENT ......................... 74 
14 PROCEDURE FOR COMPLETION AND CORRECTION OF THE CASE 
REPORT FORM .......................................................................................................... 75 
15 DIRECT ACCESS TO SOURCE DATA ..................................................................... 75 
16 DATA QUALITY ASSURANCE ................................................................................ 76 
17 ARCHIVING OF SOURCE DATA AND OTHER RECORDS ................................... 76 
18 LIABILITY AND INSURANCE ................................................................................. 76 
19 PUBLICATION POLICY ............................................................................................ 76 
20 REFERENCES ............................................................................................................ 78 


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LIST OF ABBREVIATIONS 
AE 
Adverse Event 
AESI 
Adverse Events of Special Interest 
ALT 
Alanine Aminotransferase 
AST 
Aspartate Aminotransferase 
BMI 
Body Mass Index 
CFR 
Code of Federal Regulations 
CGIC 
Clinical Global Impression of Change 
CI 
Confidence Interval 
CNS 
Central Nervous System 
COPD 
Chronic Obstructive Pulmonary Disease 
CTCAE 
Common Terminology Criteria for Adverse Events 
EQ-5D-5L 
EuroQol Group 5-Dimension Quality of Life instrument, 5-level 
version 
eCRF 
electronic Case Report Form 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HIV 
Human Immunodeficiency Virus 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Conference for Harmonisation 
IWRS 
Interactive Web Response System 
IRB 
Institutional Review Board 
mITT 
modified Intention-to-treat 
LDH 
Lumbar Disc Herniation 
LS 
Least Squares 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMRM 
Mixed Model for Repeated Measures 


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MRI 
Magnetic Resonance Imaging 
NF 
National Formulary 
NIAID/FAAN 
National Institute of Allergy and Infectious Disease Food 
Allergy and Anaphylaxis Network 
NSAID 
Non-steroidal Anti-inflammatory Drug 
ODI 
Oswestry Disability Index 
PGIC 
Patient Global Impression of Change 
PP 
Per-Protocol 
QOL 
Quality of Life 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SD 
Standard Deviation 
SF-36 
36-item Short Form Health Survey 
SLR 
Straight Leg Raise 
TEAE 
Treatment-emergent Adverse Event 
TEAESI 
Treatment-emergent Adverse Events of Special Interest 
ULN 
Upper Limit of Normal 
USP 
United States Pharmacopoeia 
VAS 
Visual Analogue Scale 
WPAI 
Work Productivity and Activity Impairment Questionnaire 


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1 INTRODUCTION 
1.1 
Background 
Lumbar disc herniation (LDH) occurs as a result of a protrusion or prolapse of the nucleus 
pulposus of an intervertebral disc into the spinal canal following partial or complete 
perforation and destruction of the posterior annulus fibrosus. The nucleus pulposus 
compresses the spinal and nerve root, causing symptoms including leg pain, low back pain, 
and numbness.(1) The principal treatment for LDH is conservative, resulting in a response in 
approximately 90% of patients.(2, 3) Conservative treatment includes rest, bed rest, medication 
(e.g., nonsteroidal anti-inflammatory drugs [NSAIDs], steroids, and muscle relaxants), corset, 
traction therapy, thermotherapy, epidural block, nerve root block, and physical therapy. 
Surgical treatment is an option for approximately 20% to 50% of the patients who do not 
respond to conservative treatment.(4, 5) To minimize 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 LDH using an enzyme, which is injected into 
the relevant intervertebral disc to reduce nerve root compression through lysis of the nucleus 
pulposus and reduction of disc pressure.(1) 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 it is currently positioned as a minimally 
invasive option after conservative treatment has failed and as an alternative to invasive 
surgery.(6, 7) Although chymodiactin (chymopapain) is approved in the United States (US) as a 
drug for chemonucleolysis, the neurological adverse events (AEs) due to its protease activity 
have been problematic.(1, 8) Therefore, development of drugs that are highly specific to the 
nucleus pulposus alone and that do not influence nerve tissue surrounding the disc is needed 
for safe and effective chemonucleolysis. 
Condoliase is a glycosaminoglycan-decomposing enzyme isolated and purified from a gram-
negative rod, Proteus vulgaris.(9) In LDH, Condoliase is thought to decompose 
glycosaminoglycan chains, thereby relieving disc pressure and compression on the spinal 
nerve root. In addition, Condoliase has the potential advantage of minimizing AEs, such as 
nerve tissue injuries in the area surrounding intervertebral discs, due to its substrate 
specificity(10) and lack of protease activity when compared with chymopapain. Seikagaku 
Corporation (SKK) is developing SI-6603, a lyophilized injectable drug containing 
Condoliase as the active ingredient for treating LDH. The phase 1/2 study (Study Number: 
SKK6603J01), phase 2/3 study (Study Number: 6603/1021), and phase 3 study (Study 
Number: 6603/1031) and a follow-up study after completion of the phase 2/3 and phase 3 


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studies (Study Number: 6603/10R2) have been completed in Japan, and a phase 2 study 
(Study Number: 6603/1121) and a phase 3 double blind study (Study Number: 6603/1131) 
have been completed in the US, and also a phase 3 open label study (Study Number: 
6603/1132) has been completed in the US and EU.  
1.1.1 Summary of Clinically Significant Findings Obtained in Nonclinical Studies and 
Clinical Studies 
A summary of nonclinical studies and prior clinical studies of SI-6603 can be found in 
Section 1 in the current edition of the investigator's brochure (IB), which contains 
comprehensive information about SI-6603. 
1.1.2 Current Study 
The current study is a Phase 3, multicenter, randomized, double-blind, sham-controlled, 
comparative study of SI-6603 in subjects with LDH. Subjects will receive a single intradiscal 
dose of SI-6603 1.25 U or a sham injection as control. Safety will be followed for 12 months 
after investigational product administration. 
1.2 
Risk and Benefit 
1.2.1 Possible Risks 
1.2.1.1 Allergic Reactions 
SI-6603 is a foreign protein, so it has the potential to cause anaphylaxis or severe allergic 
reaction. AEs such as asthma, dermatitis, drug eruption, drug hypersensitivity, eosinophil 
count increased, erythema, flushing, hand dermatitis, hypersensitivity, injection site rash, 
pruritus, pruritus generalized, rash, rash erythematous, rash generalized, rash pruritic, and 
swelling face were observed in previous clinical studies. Anaphylaxis has been reported in 
post-marketing use of SI-6603. 
1.2.1.2 Back Pain 
The most frequently reported treatment-related AE in previous studies was back pain. 
Occurrence of back pain is likely to be influenced by the primary disease; however, back pain 
occurring soon after administration of SI-6603 may be attributable to nucleus pulposus 
degradation. There are 2 potential mechanisms for this: 1) an increase in intervertebral disc 
pressure immediately after injection of SI-6603, and 2) pain associated with changes in disc 
height leading to pain from associated vertebral end plates and facet joints. 


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1.2.1.3 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 magnetic 
resonance imaging (MRI) abnormal (change in bone marrow adjacent to vertebral endplates; 
Modic change), spinal X-ray abnormal (such as intervertebral posterior angle dilation), and 
30% decrease of disc height were observed. The clinical significance of Modic changes 
remains unclear, and past SI-6603 studies did not reveal any increase in leg pain or back pain 
in conjunction with Modic changes. 
1.2.1.4 Radiation 
Risks associated with radiological imaging are well quantified.(11) The effective radiation 
dose from each radiograph performed in this study is as follows: 
During screening or follow-up visits: 
 lateral lumbar spine: 0.290 millisievert (mSv) 
 anteroposterior lumbar spine: 0.690 mSv 
The total radiation dose for each screening or follow-up visit is 1.560 mSv, for a total of 
4.7 mSv for 3 of these visits during the study. 
During the injection procedure: 
 1.25 mSv (varies depending on procedure of each site) 
X-ray imaging and the use of fluoroscopy may cause burns ranging in severity from skin 
reddening to ulcers, loss of hair in the procedural area, and delayed development of 
neoplasia. The overall radiation dose for this study is within the reasonable amount, so the 
risks associated with study-related radiation for this study are acceptable. 
1.2.1.5 Intradiscal Injection 
Temporary discomfort, injection site pain, bleeding, vascular damage, bruising, vagal 
reaction, nerve damage, disc damage, and/or infection at the injection site may occur due to 
the injection procedure. These events may also occur for the sham injection procedure even if 
the needle is not be inserted into the disc space and no placebo is injected. 
1.2.1.6 Opioid Dependence 
There is a risk that subjects who are prescribed opioid rescue could become dependent on the 
study-provided opioid, which could lead to cravings for or seeking opioids beyond those 
required during the study. The study minimizes this risk in several ways. First, only subjects 


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who were previously on opioids will be prescribed hydrocodone/acetaminophen as a rescue 
medication. Second, the subject will be limited to 60 tablets across 52 weeks. Third, 
investigators will be monitoring labs and having discussions with subjects to identify signs of 
addiction or abuse. 
1.2.2 Possible Benefits 
Nonclinical data suggest SI-6603 appears to decrease pressure in the intervertebral disc by 
reducing the high water-holding capacity of proteoglycans, leading to a volume reduction of 
the herniated disc material and a consequent reduction of pressure on the nerve root. Clinical 
data suggest that a single administration of 1.0 mL of the 1.25 U/mL, 2.5 U/mL, or 5.0 U/mL 
formulations of SI-6603 injected into the intervertebral disc relieved leg pain, the major 
complaint of patients with LDH. In the Japanese phase 2/3 and phase 3 studies, 
administration of SI-6603 1.25 U/mL demonstrated clinically significant improvement of leg 
pain and favorable improvement of back pain in LDH 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. 
1.2.2.1 Improvement of LDH Symptoms 
In the Japanese Phase 3 study, statistically significant differences were observed in the Least 
Squares (LS) mean change from baseline in worst leg pain at Week 13 in the 1.25 U dose 
group compared with the placebo group (-49.5 mm in 1.25 U group and -34.3 mm in placebo 
group on a 100 mm visual analogue scale [VAS]). This finding demonstrated the superiority 
of SI-6603 over placebo for the treatment of LDH in this study. The decrease in mean worst 
leg pain in the treatment groups also continued beyond Week 13; 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 on a 100 mm VAS. These results indicated that SI-6603 treatment led to long-term 
improvement of leg pain due to LDH.  
In addition, the LS mean change from baseline in worst low back pain at Week 13 was -28.5 
mm in 1.25 U dose group and -21.4 mm in the placebo group. The LS mean change from 
baseline in worst low back pain at Week 52 was -34.0 mm in 1.25 U dose group and -24.5 
mm in placebo group. This difference between treatment groups was not statistically 
significant, but a similar study by McGirt et al. assessing the VAS scores of 108 lumbar 
discectomy patients showed that low back pain improved from 4.6 cm before surgery to 
2.1 cm at 6 weeks after surgery, which means the change from baseline was -25.0 mm.(12) 
These results indicated that the observed improvement in low back pain with SI-6603 
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1.2.3 Rationale for Study Design, Administration Route, Dosage (Regimen), and 
Treatment Period Selection 
The result of the Japanese phase 3 study suggests that SI-6603 intradiscal injection is safe and 
effective for improving the signs and symptoms of LDH. Therefore, we plan to conduct a 
clinical study intended to evaluate the efficacy of SI-6603 1.25 U compared with control for 
the treatment of LDH. The intradiscal route was selected as the route of SI-6603 
administration for this study. The dose selected for this study is 1.25 U administered as a 
single injection into the intervertebral disc as a result of the Japanese phase 2/3 and phase 3 
study results, in which the 1.25 U dose was shown to be safe and effective. 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. Additionally, it is preferable to obtain a 
long-term effect with a single dose administration. 
LDH is treated primarily with conservative non-operative therapy; in patients who fail to 
respond to this therapy, surgery remains one of the only remaining options. Thus, the target 
population of the current study is patients who have failed conservative therapy and who have 
not received surgery. 
 


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2 OBJECTIVES 
2.1 
Primary Objective 
The primary objective is to evaluate the effectiveness of a single-dose intervertebral disc 
injection of SI-6603 at a dose of 1.25 U compared to control in subjects with LDH by 
comparing the change in worst leg pain during the past 24 hours, as assessed by VAS, from 
baseline to Week 13 after injection of the investigational product. 
2.2 
Secondary Objectives 
The secondary objectives are to evaluate the efficacy of SI-6603 1.25 U for key secondary 
endpoints, and to demonstrate whether SI-6603 1.25 U is safe and well tolerated. 
 
 


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3 STUDY DESIGN AND PLAN 
3.1 
Study Design 
This is a multicenter, randomized, double-blind, sham-controlled, comparative study. 
3.2 
Dosage/Dose Regimen 
Subjects randomized to the SI-6603 treatment group will receive a single dose injection of SI-
6603 1.25 U into an intervertebral disc. Subjects randomized to the control group will receive 
a sham injection (the needle will not be placed in the disc). 
3.3 
Study Population 
The subjects enrolled in the current study are those who have LDH and who have shown 
inadequate improvement with conservative treatment prior to screening. See Section 4 for 
additional details on the study population. 
3.4 
Duration of Study 
The study duration for each subject will be approximately 56 weeks in total. There is a 
screening period of up to 4 weeks, 1 day for treatment administration, and a follow-up period 
of 52 weeks. Screening period starts from time of informed consent and ends at time of 
randomization. 
3.5 
Study Assessments 
The primary endpoint is the change from baseline to Week 13 in average worst leg pain score 
during the past 24 hours over the previous 7 days, as assessed by 100 mm VAS. The key 
secondary endpoints are the change from baseline to Week 13 in herniation volume, change 
from baseline to Week 13 in Oswestry Disability Index (ODI) score, and change from 
baseline to Week 52 in average worst leg pain score during the past 24 hours over the 
previous 7 days, as assessed by 100 mm VAS. The incidence of treatment-emergent adverse 
events (TEAEs) and the imaging assessments for X-ray and MRI will be used to assess 
safety. Study assessments are also listed in Section 9. 
3.6 
Planned Number of Subjects 
It is planned to enroll approximately 320 subjects, 160 in the SI-6603 group and 160 in the 
control group. 
 
 


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3.7 
Randomization 
All eligible subjects will be randomized on a 1:1 basis to SI-6603 or control based on a 
computer-generated randomization schedule. The randomization will be balanced by 
randomly permuted blocks and stratified by site. 
3.8 
Study Design Schematic 
 
 
Randomization (Visit 2)
Week 26 (Visit 8) 
Week 39 (Visit 9) 
Week 52 (Visit 10) 
Visits 4 and 5: Week 2 (Day 15 ±3 days) and Week 4  
(Day 29 ±3 days)  Section 9.2.5  
Visit 6: Week 6 (Day 43 ±7 days)  Section 9.2.6  
Visit 7: Week 13 (Day 92 -7, +14 days)  Section 9.2.7 
Discontinuation visit  Section 9.2.11 
Ineligible
Screen Failure 
Screening  Section 6.2 
Subject Study Entry  Section 6.3 
Visit 2: Randomization (Day -1 or Day 1)  Section 9.2.2
Investigational Product Injection  Section 6.4 
Screening (Visit 1)  
  
Informed Consent 
Section 6.1
Screening period (Day -28 to Day -1)  Section 9.2.1 
Visit 2: Study Drug Treatment (Day 1)  Section 9.2.3 
 Week 0 (Visit 2)
  
  
  
  
Investigational Product 
Injection 
Week 1 (Visit 3) 
Week 2 (Visit 4) 
Week 4 (Visit 5) 
Week 6 (Visit 6) 
Week 13 (Visit 7) 
Discontinuation Visit 
Visit 3: Week 1 (Day 8±1 day)  Section 9.2.4 
Visit 8: Week 26 (Day 183 ±14 days) Section 9.2.8 
Informed Consent Obtained 
Randomization 
Determination on Inclusion/Exclusion Criteria 
Eligible
Visit 10: Week 52 (Day 365 ±14 days)  Section 9.2.10  
Visit 9: Week 39 (Day 274 ±14 days)  Section 9.2.9
4weeks


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4 STUDY POPULATION 
4.1 
Inclusion Criteria 
Subjects will be allowed to participate in this study only if they meet all of the following 
criteria: 
1. Subjects who have given their written informed consent to participate in the clinical study 
based on voluntary agreement after a thorough explanation of subject participation is 
provided to them. Subjects should be willing and able to provide written informed 
consent, adhere to the study visit schedule, and answer the questions on subject-
completed assessments. 
2. Male or female subjects 30 to 70 years of age, inclusive, at the time of informed consent. 
3. Subjects with contained posterolateral LDH at either L4-L5 or L5-S1 (or L5-L6): 
a. with the presence of demonstrable nerve root impingement,* as assessed by MRI; 
b. chief complaint of unilateral radiculopathy** and/or radicular leg pain 
corresponding to the ipsilateral leg and distribution of the affected nerve root; and 
c. positive result of Straight Leg Raise (SLR) test (≤70°) on the ipsilateral leg 
corresponding to the pain and distribution of the affected nerve root. The SLR 
should be performed with the subject lying flat on his/her back, and the angle 
measured relative to the horizontal plane of the examining table. 
*Judged first by the investigator, then confirmed by assessment of independent 
central image readers. 
**Defined as a condition characterized by pain radiating to some or all portions 
of the ipsilateral L5 or S1 dermatomes, which may be accompanied by 
corresponding ipsilateral weakness, sensory loss, and/or (for S1 compression) 
decreased or absent ankle (Achilles) reflex. 
4. Subjects with a current episode of radiculopathy that: 
a. is symptomatic only in the unilateral leg and with a distribution corresponding to 
that of the affected nerve root, and  
b. has been present for 6 weeks or more but 12 months or less, and  
c. which is still ongoing at the time of informed consent. 


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Note: Subjects may have had similar past episodes involving the same nerve 
root; in this case, however, the most recent past episode must have 
ended at least 3 months prior to the onset of the current episode. 
5. Subjects with inadequate improvement in pain caused by LDH despite 6 weeks or more 
of conservative treatment,* which is still ongoing at the time of informed consent. 
*Conservative treatment is pharmacotherapy (e.g., steroids, NSAIDs, or non-opioid 
analgesics), physical therapy, chiropractic, acupuncture, spinal injection, epidural 
injection, or nerve block. For spinal injection, an inadequate response over a 4-week 
period can be counted toward the required ≥ 6 weeks of conservative treatment. 
6. Subjects whose worst leg pain (100 mm VAS) for the 7 consecutive days up to the day 
before randomization meets following conditions: 
a. worst leg pain scores have been recorded for at least 5 out of the 7 days; 
b. the mean of the worst leg pain scores is 50 to 90 mm; and 
c. the range of fluctuation in worst leg pain scores over the 7 days (difference 
between minimum and maximum scores) is ≤ 25 mm. 
7. Subjects who can comply with the rules of concomitant medications (See Section 6.6) and 
therapies (See Section 6.7) usage as defined in the protocol. 
8. Subjects who can comply with the rules of rescue medication usage as defined in the 
protocol (See Section 6.6.4) and, for those who qualify to receive rescue medication 2 
(hydrocodone/acetaminophen), are not at high risk of opioid abuse, as determined by the 
investigator. 
9. Subjects with ≥30% on the ODI at the time of randomization. 
4.2 
Exclusion Criteria 
Subjects will not be allowed to participate in this study if they meet any of the following 
criteria: 
1. Subjects who have LDHs demonstrating clear impingement to the nerve root* at 2 or 
more levels as assessed by MRI and possessing symptoms corresponding to the 
distribution of the affected nerve root. 
*Judged first by the investigator, then confirmed by assessment of independent central 
image readers. 
2. Subjects with a contraindication to receive MRIs (e.g., pacemaker or other metallic 
implants not compatible with MRI). 


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3. Subjects demonstrating LDH as described below in the disc to be treated, as assessed by 
MRI*: 
a. rupture into the posterior longitudinal ligament (those with transligamentous 
extrusion or sequestration [free fragment]-type LDH); 
b. isolated central herniation; 
c. anterolateral herniation; and/or 
d. extraforaminal herniation. 
*Judged first by the investigator, then confirmed by assessment of independent 
central image readers.  
4. Subjects demonstrating clinical symptoms of radiculopathy (e.g., sciatica, weakness, 
sensory loss, or positive result of SLR test [≤70°]) caused by LDH on the contralateral 
leg. 
5. Subjects who, within 28 days prior to randomization, have: 
a. received a block procedure (e.g., spinal injection, epidural injection or nerve 
block) for treatment of LDH; and/or 
b. received oral or injectable corticosteroids to the back, buttock, or 
posterior/lateral aspects of the affected leg.  
Note: Inhaled, nasal, or topical steroids used over small areas of skin (e.g., < 
100 cm2) is permitted. 
6. Subjects who, within 7 days prior to randomization, have:  
a. taken opioids (including tramadol, tapentadol, meperidine, or opioid-
containing combination products) by any route of administration;  
b. taken cannabis by any route of administration; and/or 
Note: Use of CBD oil that contains regulated quantities of 
tetrahydrocannabinol (i.e., psychoactive CBD oil preparations) is 
prohibited; amounts of THC resulting in a positive drug test will be 
disqualifying. 
c. received local anesthesia to the back, buttock, or posterior/lateral aspects of 
the affected leg (local anesthesia to the back during SI-6603 injection 
procedure is permitted). If the local anesthesia was part of a block procedure, 
exclusion criterion 5 applies. 


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Note: The protocol permits enrollment of otherwise qualifying subjects who are on 
opioids immediately prior to screening and who are willing to switch to 
hydrocodone/acetaminophen as an on-study rescue medication. However, it is 
possible and permissible that some sites may elect not to enroll such subjects 
for logistical or other reasons. 
7. Subjects who currently have any of the following conditions: 
1) low back pain caused by disorders other than LDH;  
2) mean of worst low back pain assessed by VAS for 7 consecutive days up to the 
day before randomization is > 90 mm; or; 
3) mean of worst low back pain assessed by VAS for 7 consecutive days up to the 
day before randomization is > 10 mm higher than the mean of worst leg pain. 
Note: For low back pain assessment by VAS for 7 consecutive days up to the 
day before randomization, at least 5 out of 7 days need to be entered. 
8. Subjects who are pregnant or breast-feeding, or women of childbearing potential with a 
positive serum or urine pregnancy test(s). 
Pregnancy tests will not be required for female subjects who have undergone a 
hysterectomy and/or bilateral tubal ligation, or who are postmenopausal (have not 
menstruated within the past 2 years). 
9. Sexually active female subjects of childbearing potential who have a male partner and are 
not willing to use adequate contraceptive measures to avoid pregnancy until the end of the 
study. Sexually active male subjects with female partners who are not willing to use 
adequate contraceptive measures until Week 13 of the study. 
Adequate methods of birth control include the following: 
a. Hormonal contraception (female subjects) or use of at least one acceptable 
double-barrier method. Acceptable double barrier methods include the following: 
i. diaphragm plus a spermicidal agent; or 
ii. condoms (male or female) plus a spermicidal agent. 
b. Vasectomy, hysterectomy, bilateral tubal ligation, intrauterine device, and/or an 
exclusive sexual partner for whom one of these methods applies. 
Female subjects who have undergone hysterectomy and/or bilateral tubal ligation, or are 
postmenopausal (have not menstruated within past 2 years) do not need to practice birth 
control. 


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10. Subjects who have undergone a lumbar operation, lumbar percutaneous nucleotomy, or 
lumbar intradiscal therapies (e.g., chemonucleolysis or intradiscal electrothermal 
treatment) at the affected level of lumbar spine, or surgery at any other lumbar spine level 
with persistent symptom(s) including failed back surgery syndrome. 
11. Subjects with any of the following: 
a. X-ray imaging findings of vertebral body angle formed by flexion ≥5°, and/or 
spondylolisthesis (vertebral body translation ≥3 mm)* in the disc to be treated; 
b. Any of the following spinal related disorders*: spondylosis deformans, 
degenerative spondylolisthesis, spinal deformity (scoliosis: Cobb angle >20° 
or lordosis [L1-S1]: Cobb angle <20°), spinal tumor, diskitis, vertebral 
fracture adjacent to the disc to be treated, bony stenosis with nerve root 
impingement at L3-L4, L4-L5 or L5-S1, or severe lumbar degenerative disc 
disease in the disc to be treated; 
c. Any of the following spinal related disorders* associated with low back pain 
that would interfere with safety or efficacy evaluations: spinal canal stenosis 
(except for stenosis caused by LDH), spondyloarthritis, ankylosing 
spondylitis, vertebral fracture in the lumbar spine, significant degenerative 
disease of the facet joints, or other disorders of the lumbar spine; 
d. Presence of osteophytes in the lumbar spine (Nathan's classification ≥3rd 
degree).* 
*Judged first by the investigator, then confirmed by assessment of 
independent central image readers. 
12. Subjects with history, diagnosis, signs or symptoms of disorders that, in the investigator’s 
opinion, is likely to interfere with pain efficacy assessments.  
Examples may include: chronic pain disorders (e.g., fibromyalgia, restless legs 
syndrome), peripheral neuropathy caused by certain disorders (e.g., diabetes), Parkinson's 
disease, complex regional pain syndrome, osteoarthritis (unless symptoms are only in the 
upper extremities), osteoporosis, spondyloarthritis, ankylosing spondylitis, rheumatoid 
arthritis, or gout. 
13. Subjects with any history of any psychosis or psychotic disorder (includes schizophrenia 
and bipolar I disorder), or subjects with any nonpsychotic psychiatric disorder, including 
known personality disorders, that has been sufficiently severe to cause functional 
impairment within 6 months prior to screening. This latter exclusion is not intended to 
exclude subjects with depression or anxiety that does not cause functional impairment or 


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who are adequately treated with antidepressant or anxiolytic medication at doses that are 
not expected to change during the course of the trial. 
14. Subjects with history within the last 5 years of substance abuse or dependency, including, 
but not limited to, alcohol, opioids, cannabis (even where legal), and prescribed Central 
Nervous System (CNS) stimulants or depressants.  
15. Subjects with alcohol consumption in excess of an average of 2 drinks per day (1 unit = 
12 ounces of beer, 5 ounces of non-fortified wine, or 1.5 ounces of 80-proof liquor). 
16. Subjects who meet either of the following conditions: 
a. Subjects who cannot wash-out opioids or cannabis for relief of pain, and 
cannot remain free of these prohibited medications during the course of the 
trial; 
b. or subjects who have opioid withdrawal symptoms. 
17. Subjects who test positive at screening or randomization for drugs of abuse, including 
(but not limited to) opioids, amphetamines (even when prescribed), cocaine, and 
cannabinoids (even where legal, prescribed, or possibly due to use of CBD oil). A 
positive result for benzodiazepine may be permissible if, in the investigator’s opinion, is 
the result of appropriate use of a prescribed medication. A positive result for opioids or 
cannabinoids at screening, but not baseline, is permissible if, in the investigator’s opinion, 
the result is from opioids or cannabinoids taken before screening and which have since 
been stopped and will not be resumed during the study, except as specified for rescue 
medication (See Section 6.6.4). Exclusionary urine drug tests are considered conclusive 
and may not be repeated. 
Note:  Subjects should be advised that they should not submit for urine drug testing 
if they have taken any opioids in the preceding 3 days or are using any of the 
prohibited drugs. Subjects should not be urine drug tested if there is any 
reported or known prohibited drug use or opioid use within the preceding 3 
days. 
18. Subjects who test positive for alcohol on the blood alcohol test at screening. Subjects 
should be informed that they must not drink alcohol within 12 hours of the screening 
blood test, and should not take the test if they have done so. A positive blood alcohol test 
cannot be repeated. 


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19. Subjects 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. 
20. Subjects with neurological disorders, including cauda equina syndrome that is severe or 
that demonstrates rapid progression, and subjects who have had a seizure in the past 
5 years or who are taking anticonvulsant medications for any reason other than 
neuropathic pain. 
21. Subjects with motor weakness graded less than 4 (Medical Research Council Scale <4). 
22. Subjects with human immunodeficiency virus (HIV), or a current, active, clinically 
significant systemic infection requiring treatment with antibiotics, antivirals, or 
antifungals. 
23. Subjects with the following medical conditions or diseases: 
a. clinically significant disorders such as uncontrolled pulmonary disease (e.g., 
asthma, chronic obstructive pulmonary disease [COPD]), uncontrolled 
hypertension, type I or uncontrolled type II diabetes, or other serious heart, liver, 
kidney, or blood disease or immunodeficiency. 
b. clinically evident cerebrovascular disease, pulmonary infarction, congestive heart 
failure, or arrhythmia (e.g., excludes normal sinus rate variations and atrial or 
ventricular ectopy ≤2/min). 
c. history or signs of coronary artery disease with or without angina pectoris or 
myocardial infarction within the last 6 months. 
24. Subjects who have difficulty receiving injection of investigational product, or subjects 
with a tendency to bleed or with bleeding disorders such as (but not limited to) 
hemophilia, aplastic anemia, cirrhosis of the liver, leukemia, thrombocytopenia, and 
vitamin K deficiency. Subjects using medication for the purpose of anticoagulation, 
including heparin and warfarin, which cannot be reversed preoperatively will also be 
excluded. 
25. Subjects with medical conditions and/or diseases that the investigator believes could 
affect the study results or interfere with safe conduct of the study. 
26. Subjects who meet any of the following criteria: 
a. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) ≥2.5x 
upper limit of normal (ULN) 


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b. Total bilirubin ≥1.5 x ULN, unless isolated Gilbert’s syndrome 
c. Serum creatinine ≥1.5 x ULN 
d. Hepatitis C virus antibody or hepatitis B surface antigen positive.  Subjects 
who have been successfully treated for hepatitis C and currently have 
undetectable HCV RNA are eligible for study participation. 
27. Subjects with a body mass index (BMI) ≥40. 
28. Subjects who have difficulties securing an investigational product injection route by the 
investigator for anatomical reasons. 
29. Subjects who are currently hospitalized or have a planned hospitalization during the life 
of the study. 
30. Subjects who have a planned move that may result in difficulty visiting a clinical site(s) 
during the life of the study. 
31. Subjects who previously participated in a clinical study of SI-6603. 
32. Subjects who are receiving compensation according to the Workers' Compensation Act or 
are involved in personal injury litigation due to a lumbar-related injury. 
33. Subjects who participated in another interventional clinical study within 30 days prior to 
the time of informed consent, or who are expected to participate in another study during 
the period of this study. 
5 SUBJECT WITHDRAWAL FROM THE STUDY 
5.1 
Criteria for Subject Withdrawal 
The investigator will withdraw a subject from the clinical study if any of the following 
situations occur: 
1. When the occurrence of an AE or other safety concern leads the investigator to judge it 
inadvisable for the subject to continue the clinical study; 
2. When a poor response to the investigational product leads the investigator to judge it 
difficult or inadvisable for the subject to continue the clinical study, such as using the 
prohibited block procedure for treating LDH before Week 13 or receiving surgery to treat 
LDH at any time over the course of the study; 
3. Subjects who test positive for drugs of abuse, including (but not limited to) opioids [other 
than hydrocodone or its metabolites (hydromorphone, nor hydrocodone) when 


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hydrocodone is being prescribed within this study], amphetamines (even when 
prescribed), cocaine, and cannabinoids (even where legal, prescribed, or possibly due to 
use of CBD oil). A positive result for benzodiazepine may be permissible if, in the 
investigator’s opinion, is the result of appropriate use of a prescribed medication.  Truly 
equivocal urine drug screen results, should they occur, must be discussed with the 
medical monitor for a decision on subject disposition. 
Subjects who are withdrawn from the study as a result of testing positive for drugs of 
abuse (other than allowed hydrocodone) will be offered a referral for follow up at a drug 
treatment facility. 
4. When a protocol deviation or pattern of deviations lead the investigator to judge it 
difficult or inadvisable for the subject to continue the clinical study or is likely to 
significantly confound the study safety or efficacy results; 
5. When the subject chooses to discontinue from the clinical study; 
6. When the subject is lost to follow-up; or 
7. Any other reason that, in the documented opinion of the investigator, makes continued 
study participation unfavorable for the subject or for study integrity. 
 
5.2 
Procedures for Subject Withdrawal 
Subjects 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 subject 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 subject withdraws consent and still agrees to undergo a 
final examination, this will be documented in the eCRF. A subject may also be withdrawn 
from the study by the investigator, sponsor, regulatory authority(ies), or an Institutional 
Review Board (IRB). Subjects will also be withdrawn if the entire study is terminated 
prematurely. Withdrawn subjects will not be replaced. 
5.3 
Post-treatment Surgery Follow-up for Withdrawn Subjects 
Subjects withdrawn from the study will be followed by investigators until 52 weeks after 
injection to gather data about post-treatment surgery. Information about post-treatment 


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surgery will be collected for following surgery types: 
 Post-treatment surgery for treatment of LDH at the same level of administration of the 
investigational product; 
 Post-treatment surgery for treatment of LDH at a different level than administration of 
the investigational product; and  
 Post-treatment lumbar surgery not for treatment of LDH. 
6 STUDY METHOD AND PROCEDURES 
6.1 
Informed Consent 
Before each subject is admitted to the study, informed consent will be obtained from the 
subject according to the regulatory and legal requirements of the participating country/state. 
This consent form must be signed, 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. When consent is obtained must also 
be documented in the subject source record and eCRF. 
If a protocol amendment is required, the informed consent form (ICF) may need to be revised 
to reflect the changes to the protocol. If the ICF is revised, it must be reviewed and approved 
by the appropriate IRB and signed by all subjects subsequently enrolled in the study as well 
as those currently enrolled in the study, except for when the change is administrative or 
resigning is not required per the IRB. 
[Pre-screening Visit] 
Before each subject is screened for the study, a pre-screen informed consent can be obtained 
from the subject for the purpose of conducting a detailed assessment of subject eligibility on 
an as-needed basis. This consent form must be signed, dated, and retained by the investigator 
as part of the study records and a copy must be provided to the subject. When a subject has 
signed a pre-screen consent form, the investigator can conduct pre-screening for procedures 
and assessments considered necessary for the subject’s eligibility assessment (e.g., 
neurological examination, pain assessment, imaging assessment). These procedures and 
assessments can be set based on the investigator’s decision. During the pre-screening period, 
the investigator or delegated site staff can collect X-ray and MR images and transmit them to 
the central imaging facility according to a separate procedural manual. MRI and X-ray 
images are not required to be repeated as long as these images were previously acquired 
within 56 days prior to the randomization date. 


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6.1.1 Subject Identification 
At the screening visit, a unique subject number will be assigned consecutively for each 
subject after he or she signs the ICF. For subjects going through pre-screening, such subjects 
will be assigned with unique subject number for purpose of pre-screening. 
6.2 
Screening 
6.2.1 Central Imaging Eligibility Assessment 
The investigator will confirm the subject’s eligibility based on the X-ray and MR images and 
clinical symptoms at screening. When the investigator judges that the subject is eligible, the 
investigator will submit the images to the central imaging facility. The central imaging 
facility will perform the central eligibility assessment and issue a report including the results. 
The investigator will comply with the central imaging facility result in judging the subject’s 
eligibility. The detailed method for central imaging eligibility assessment will be provided in 
a separately distributed manual. 
6.2.2 Handling of Concomitant Medications 
The investigator will confirm all medications being taken by the subject (including those for 
treatment of LDH) during the screening visit. If a subject is taking any prohibited 
medication(s) described in Section 6.6.1, the medication should be washed out at screening. 
Subjects are permitted to switch their medications to other restricted concomitant medications 
described in Section 6.6.2 if washout is necessary. The investigator should record the names, 
doses, and dosing regimens of all medications the subject is taking at screening, noting 
whether these medications will be taken through the course of the study (only if allowable) or 
whether they will be discontinued at screening. For medications that will be discontinued, the 
date of the last dose must be recorded. 
6.2.3 Subject Daily Diary 
For each subject, site staff will set up an electronic subject diary, give an explanation of the 
diary to the subject, and confirm that the subject is able to operate the electronic subject diary 
adequately, according to a separately distributed manual. Site staff will remind the subject to 
record entries in their diary every day basically before going to bed and will confirm subject 
eligibility based on the pain intensity recorded during the screening period. 
6.2.4 Re-screening 
Re-screening of subjects may be allowed in circumstances where both of the following 
conditions are met: 


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1) In the investigator’s opinion, the subject is likely to fully qualify for study 
participation, despite the previous screen failure, because either “a” or “b” below 
applies:   
a. The evaluation(s) being repeated initially yielded an equivocal or 
uninterpretable result and repeating the evaluation is likely to give more 
definitive results OR the evaluation(s) being repeated initially yielded a result 
that is likely to be transient and inconsequential (e.g., subject is actively losing 
weight on a diet but today has a BMI of 40.1 [≥ 40.0 is exclusionary]). 
 Note: Exclusionary urine drug tests may not be repeated. 
b. Previous MRI and X-ray images were deemed eligible, needing clinical 
correlation, or not read by central imaging facility during the initial screening 
attempt OR required images were deemed of unacceptable quality but could 
not be repeated within the screening window. 
2) Approval in writing (email) is obtained from the medical monitor after medical 
monitor is fully apprised of the screening findings and reason(s) for the re-screening 
request. 
During the re-screening period, MRI and X-ray images are not required to be repeated as long 
as these evaluations were previously performed within 28 days prior to the re-screening 
informed consent (Visit 1) date.  
 
6.3 
Subject Study Entry 
At the time of each subject’s entry into the study, the investigator will perform all the 
examinations described in Section 9.2.1 and confirm that the subject is eligible for the study. 
Each subject who is judged as eligible for the study by the investigator will be enrolled into 
the study. 


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6.3.1 Allocation/Randomization of Subjects to Treatment 
Randomization of a subject to treatment will occur after all screening procedures have been 
performed and the subject’s eligibility for the study has been confirmed. Each randomized 
subject will receive a unique randomization number. Randomized subjects who terminate 
their study participation for any reason, regardless of whether investigational product was 
taken or not, will retain their randomization numbers. The Interactive Web Response System 
(IWRS) will assign subjects to treatment groups based on the predefined randomization list. 
6.4 
Investigational Product or Sham Injection Procedure 
At Visit 2 (Week 0), randomized study subjects will receive either a single injection of SI-
6603 or a sham injection by an unblinded injector. For subjects in the active treatment group, 
a vial of SI-6603 for injection 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 injected into the intervertebral disc in 
a single dose. For subjects in the control group, a solution will not be prepared and the needle 
will not be placed in the intervertebral disc. The sham injection procedure should be 
comparable to that of the active treatment procedure. The unblinded investigator who injected 
the investigational product must save the images taken during injection that specifically show 
needle placement during the procedure. The detailed method for administration will be 
provided in a separately distributed manual. 
6.5 
Treatment Blinding 
The study will be performed in a double-blind manner. The investigator will develop a 
procedure for maintenance of blinding at the site in accordance with the criteria outlined in a 
separately distributed manual and documented in the site’s blinding plan. Only the physician 
who performs the injection and the unblinded study coordinator will be unblinded and will 
not discuss any aspects of the procedure with the subject or other blinded study site 
personnel. Additionally, the physician performing the injection will not be involved in any 
other study procedure except for imaging assessment before injection or have any additional 
subject contact. 
The study blind should not be broken except in a medical emergency (where knowledge of 
the investigational product received would affect the treatment of the emergency) or 
regulatory requirement. Blinding will be maintained in accordance with a separately 
distributed manual. 


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6.6 
Concomitant Medications 
6.6.1 Prohibited Medications 
Use of the following medications are prohibited after wash-out. Prohibited concomitant 
medications include the following: 
[Prohibited in any forms] 
 Opioids (including tramadol, tapentadol, meperidine, and opioid-containing 
combination products) except as described in rescue medication Section 6.6.4) 
 Cannabis (even where legal) 
Note: Use of CBD oil that contains regulated quantities of tetrahydrocannabinol 
(i.e., psychoactive CBD oil preparations) is prohibited; amounts of THC 
resulting in a positive drug test will be disqualifying.  
[Prohibited in specific forms] 
 Oral and injectable corticosteroids to the back, buttock, or posterior/lateral aspects of 
the affected leg. 
Note: Inhaled, nasal, or topical steroids used over small areas of skin (e.g., < 100 
cm2) is permitted. 
 Local anesthesia to the back, buttock, or posterior/lateral aspects of the affected leg.  
Note: Local anesthesia to the back during the investigational product injection 
procedure is permitted. 
Subjects should also suspend the use of over-the-counter medications that may contain any 
active ingredient(s) described above.  
For further details, see medication listings that will be separately distributed. 
6.6.2 Restricted Concomitant Medications 
Subjects who had been taking restricted concomitant medications to treat LDH at stable dose 
and regimen for at least 7 days prior to randomization may be enrolled in the study. These 
restricted concomitant medications include NSAIDs, acetaminophen, muscle relaxants, 
medicines for neuropathic pain (e.g., pregabalin, gabapentin), and medicines for depression 
used to treat LDH. Medications stated as restricted concomitant medications for purpose of 
use other than to treat LDH should also remain in stable dose.  
Throughout the follow-up period, subjects are allowed to reduce the amount of their restricted 
medication drug after injection by consultation with investigators, but they must not add a 
medication or increase a dose once it is decreased.  


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All restricted concomitant medications used on an as-needed basis (except for rescue 
medications) are prohibited. 
For further details, see medication listings that will be separately distributed. 
6.6.3 Medication Use Before, After or During the Injection Procedure 
If subjects are required to stop use of any restricted concomitant medications temporarily 
prior to injection, such restricted concomitant medication can be resumed with same 
dose/dosage after the injection. However, such subjects can only stop medication within 2 
days prior to date of randomization.  
Conscious sedation with non-opioid medications is permitted for the injection procedure 
and/or imaging procedure when necessary for subject comfort or safety. Use of prohibited 
medication (e.g. inhalational anesthetics, opioids including fentanyl or morphine) before, 
after or during the injection procedure is not allowed. Use of rescue medication 2 
(hydrocodone/acetaminophen) after the injection procedure is allowed. 
For the purpose of managing post-injection pain and if the use of rescue medication 1 
(acetaminophen) is not sufficient for pain control, it is permissible to add or increase the dose 
of an NSAID for pain or a muscle relaxant for muscle spasm during the 3-day post-injection 
period. 
6.6.4 Rescue Medications 
[Acetaminophen (rescue medication 1)] 
Subjects will be provided with acetaminophen at each clinic visit to use as a rescue 
medication 1 for breakthrough pain resulting from LDH or for treatment of AEs. Subjects 
will be instructed to use the acetaminophen only if the pain has sufficient severity to require 
use of the rescue medication.  
Subjects will be advised to limit their total acetaminophen use to 3,000 mg/day. Subjects will 
also be reminded not to use other medications that contain acetaminophen, such as cold or 
allergy medications, as this may cause them to consume more than 3,000 mg of 
acetaminophen in 1 day. 
Subjects will also be asked to bring the acetaminophen container(s) with any remaining 
tablets every visit. If a subject has enough remaining acetaminophen, additional medication 
will not be provided. 
 
 


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[Hydrocodone/acetaminophen (rescue medication 2): limited to opioid users at study start] 
Hydrocodone/acetaminophen will be prescribed as rescue medication 2 only for subjects who 
are using prescribed opioids at the time of informed consent (or documented within the past 2 
months).  Further, in order to participate, these subjects must be willing to wash-out of their 
current opioid therapy (See Section 4.2) and, when not already prescribed 
hydrocodone/acetaminophen, switch to hydrocodone/acetaminophen for the duration of the 
study. These subjects may be prescribed up to 60 hydrocodone/acetaminophen (5mg/300-
325mg) tablets to use as a rescue medication 2 through the end of the study. 
Subjects will be instructed that the hydrocodone/acetaminophen should be used on a limited 
basis and only when acetaminophen alone fails to adequately relieve pain. Further they will 
be instructed that they should wait at least 4 hours after using acetaminophen before they 
dose with hydrocodone/acetaminophen.  
Subjects will be allowed to take hydrocodone/acetaminophen at 1 - 2 tablets every 4 to 6 
hours as needed for severe pain, but not to exceed 4 tablets per day. Subjects will be advised 
to limit their total acetaminophen use to 3,000 mg/day. As such, subjects will be reminded 
not to use other medications that contain acetaminophen, such as cold or allergy medications, 
as this may cause them to consume more than 3,000 mg of acetaminophen in 1 day. 
During each of the consecutive 7 days prior to Visit 6 (Week 6), Visit 7 (Week 13), Visit 8 
(Week 26), Visit 9 (Week 39), and Visit 10 (Week 52), the use of 
hydrocodone/acetaminophen is prohibited. For Visit 7 (Week 13) and Visit 10 (Week 52), 
subjects will be instructed to suspend use of hydrocodone/acetaminophen 10 days prior to 
those visits. As noted in the exclusion criteria, no opioid use of any kind is allowed within the 
7 days prior to Visit 2 (Week 1) (See Section 4.2). 
Hydrocodone/acetaminophen will be prescribed at a maximum of 28 tablets per prescription 
and not to exceed total of 60 tablets during the study. Subjects will also be asked to bring the 
hydrocodone/acetaminophen container(s) with any remaining tablets to every visit. If a 
subject has enough remaining hydrocodone/acetaminophen to last until the next scheduled 
visit, additional medication will not be provided. 
 
6.7 
Concomitant Therapies 
6.7.1 Prohibited Concomitant Therapies 
Lumbar operation, lumbar percutaneous nucleotomy, or lumbar intradiscal therapies (e.g., 
chemonucleolysis, intradiscal electrothermal treatment) for treatment of symptoms caused by 


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LDH, such as low back pain and leg pain, are prohibited throughout the study. Block 
procedures (e.g., nerve block, epidural block, or facet block) for treatment of symptoms 
caused by LDH is prohibited before Week 13. If a subject is to receive a prohibited 
concomitant therapy during the study, they should return to the site for a discontinuation visit 
and be discontinued from the study. 
6.7.2 Restricted Concomitant Therapies 
Subjects who had been receiving physical therapy (e.g., exercise therapy, thermotherapy, 
braces, acupuncture, manipulative treatment, transcutaneous electrical nerve stimulation) to 
treat LDH beginning 7 days or more prior to randomization may continue with that therapy 
during the study only if the frequency and intensity will not be changed. Subjects are allowed 
to reduce the frequency or intensity after injection by consultation with investigators, but they 
must not add new therapy or increase a frequency or intensity once it is reduced. 
6.7.3 Lifestyle Restrictions 
Subjects will be instructed by the site about any lifestyle or activity restrictions following the 
injection procedure, such as avoiding strenuous activities. Specific instructions will be 
provided in a separately distributed manual. 
7 INVESTIGATIONAL PRODUCT 
7.1 
Identity of Investigational Products 
7.1.1 SI-6603 
SI-6603 will be administered as a lyophilized injection that, when reconstituted with 1.2 mL 
of saline, provides 1.0 mL of solution containing the ingredients listed below: 
Ingredient
Active ingredient
SI-6603
Inactive ingredients 
Monosodium phosphate dihydrate
(United States Pharmacopoeia [USP])
Disodium hydrogen phosphate, dodecahydrate (USP)
Sucrose (National Formulary [NF])
Polyethylene glycol 3350 (NF)
SI-6603 for injection (1.25 U [1.5 U/vial]) will be manufactured for reconstitution with 
1.2 mL of saline for delivery of 1.25 U in 1.0 mL. 
7.1.2 Control 
The control group subjects will receive a sham injection. Boxes including empty vials with an 
identical label to boxes containing SI-6603 will be shipped as investigational products for use 
in the sham injections. 


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7.2 
Packaging and Labeling 
Investigational product will be packaged by the vendor according to all local legal 
requirements and applicable regulatory requirements. 
7.3 
Preparation, Handling, Storage, and Accountability 
All investigational product supplies must be stored in the original boxes in accordance with 
the manufacturer’s instructions (2 to 8°C and shielded from light). Investigational product 
must be stored in a securely locked area, accessible to authorized personnel only. The 
investigator is responsible for maintaining accurate investigational product accountability 
records throughout the study. Individual subject dispensing of investigational product must be 
documented in the subject source record and eCRF. The investigator is responsible for 
returning all used or unused investigational product in the original boxes to the sponsor or 
designee and must verify that no remaining supplies are in the investigator’s possession.


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8 ENDPOINTS 
8.1 
Efficacy Endpoints 
8.1.1 Primary 
The primary endpoint is the change from baseline to Week 13 in average worst leg pain score 
during the past 24 hours over the previous 7 days, as assessed by 100 mm VAS. 
8.1.2 Key Secondary 
The key secondary efficacy endpoints for this study are as follows: 
 Change from baseline to Week 13 in herniation volume 
 Change from baseline to Week 13 in ODI score 
 
Change from baseline to Week 52 in average worst leg pain score during the past 
24 hours over the previous 7 days, as assessed by 100 mm VAS. 
8.1.3 Other Secondary 
The other secondary efficacy endpoints for this study are as follows: 
 Change from baseline in worst leg pain score at each time point 
 Change from baseline in worst low back pain score at each time point 
 Change from baseline in ODI score at each time point 
 Percentage of subjects with negative SLR test 
 Percentage of subjects without hypoesthesia, muscle weakness or hyporeflexia 
 Patient Global Impression of Change (PGIC) score at each time point 
 Clinical Global Impression of Change (CGIC) score at each time point 
 Change from baseline in 36-item Short Form Health Survey (SF-36) scores at each 
time point 
 EuroQol Group 5-Dimension Quality of Life instrument, 5-level version (EQ-5D-5L) 
quality of life (QOL) score and VAS score at Week 13 and Week 52 
 Work Productivity and Activity Impairment Questionnaire (WPAI) score at Week 13 
and Week 52 
 Incidence and amount of rescue medication use over 13 weeks 
 Change from baseline in amount of rescue medication use at each time point 
 Cumulative distribution of percentage change from baseline in worst leg pain score at 
Week 13 and Week 52 


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 Cumulative distribution of percentage change from baseline in ODI score at Week 13 
and Week 52 
 Responder rate by composite definition*1 at Week 13 
 Change from baseline in intervertebral disc volume at Week 13 and Week 52  
 Change from baseline in herniation volume at Week 13 and Week 52 
 Incidence of post-treatment surgery for LDH at the same level of investigational 
product injection 
 Number of subjects with recurrence of LDH*2 at Week 52 
*1 A subject who meets all 4 criteria below (A, B, C, and D) as assessed at Week 13: 
A. A reduction of 30% in worst leg pain score during the past 24 hours assessed 
by VAS from baseline to Week 13; 
B. Improvement of 30% in ODI score from baseline to Week 13; 
C. Maintenance or improvement of neurologic status (motor, sensory, reflexes) 
from baseline to Week 13; and 
D. No “Treatment Failure” 
 
“Treatment Failure” is defined as a subject to whom any of the conditions 
shown below become applicable until Week 13 after investigational product 
injection: 
i. 
Use of additional medication/therapy to treat TEAEs or 
complications associated with LDH 
- 
New prohibited medications used for more than 7 days; 
- 
Increase of restricted medications used for more than 7 days; 
- 
Use of new prohibited therapies; or 
- 
Increase in frequency or intensity of restricted therapies. 
ii. 
Poor response to investigational product that leads the investigator to 
judge it necessary to perform a surgical intervention for back pain/leg 
pain or withdraw from the study 
iii. 
Increase of measurement value on either vertebral body angle formed 
by flexion or vertebral body translation from baseline to values: 
- 
Vertebral body angle formed by flexion of ≥5º, or 


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- 
Vertebral body translation of ≥3 mm 
iv. 
Occurrence of treatment-related AEs that lead the investigator to judge 
it necessary for the subject to have surgical intervention or withdraw 
from the study 
*2 Recurrence of LDH is defined as below: 
 
A subject who has all of the following conditions: 
a. The subject shows improvement according to all of the following clinical 
symptoms at Week 13: 
- 
Reduction of 30% in worst leg pain score from baseline, 
- 
Improvement of 30% in ODI score from baseline, and 
- 
Maintenance or improvement of neurologic status (motor, sensory, 
reflexes) from baseline; 
b. The subject does not show with any improvement of worst leg pain score, 
ODI score, or neurologic status at Week 52 or discontinuation visit; and 
c. The subject has been judged by the investigator as a “Treatment Failure” 
for efficacy reason(ii), as described above. 
8.2 
Safety Endpoints 
The following safety endpoints will be assessed after investigational product administration: 
 Adverse events 
 Laboratory tests 
 Vital signs 
 Imaging assessments by X-ray and MRI 
- 
Disc height (disc index) 
- 
Vertebral body translation 
- 
Vertebral body angle formed by flexion 
- 
Modic classification 
 Occurrence of post-treatment lumbar surgery 
- 
Surgery for treatment of LDH at a different level than administration of the 
investigational product 
- 
Lumbar surgery not for treatment of LDH 
 


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9 STUDY SCHEDULE AND VARIABLES 
9.1 
Schedule of Activities 
The schedule of study activities is provided in Table 1. 
Table 1  
Schedule of Study Activities 
Pre-
screening 
Screening 
Follow up 
Visit
 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
DC 
Week
 
-4 
0 
1 
2 
4 
6 
13 
26 
39 
52 
≤ 
13 >13 
Day
 
-28 
1 
8 
15 
29 
43 
92 
183
274
365
 
 
 
 
 
Before 
Injection 
 
After 
Injection
 
Window (days)
 
 
-1 
 
 
±1 
±3 
±3 
±7 -7, +14 ±14
±14
±14
 
 
Informed consent 
Xk 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
Xk 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics, medical 
history 
Xk 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant medications/ 
rescue medication use 
 
X 
X 
X
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital signs 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse events 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine drug test 
 
X 
X 
 
 
Xl 
Xl 
Xl 
Xl 
Xl 
Xl 
Xl 
 
 
 
Neurological examination 
Xk 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Laboratory testsa 
 
X 
 
 
 
X 
 
 
X 
X 
 
 
 
X 
 
Pregnancy testb 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Imaging (X-ray, MRI) 
Xk 
Xc 
 
 
 
 
 
 
 
Xd 
 
 
Xd 
Xd 
Xd
Central eligibility 
assessment for imaging 
Xk 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Confirmation of washout 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Daily diary (VAS pain 
assessment and rescue 
medication use) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Subject educatione 
 
X 
 
 
X 
 
 
 
X 
 
 
X 
 
 
 
Distribution of rescue 
medication 
(acetaminophen)f 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Distribution of rescue 
medication (hydrocodone/ 
acetaminophen)f 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
ODI 
 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
SF-36 
 
 
X 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
EQ-5D-5L 
 
 
X 
 
 
 
 
 
 
X 
 
 
X 
X 
X 
WPAI 
 
 
X 
 
 
 
 
 
 
X 
 
 
X 
X 
X 
Randomizationg 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Injectionh 
 
 
 
X
 
 
 
 
 
 
 
 
 
 
 
PGIC 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CGIC 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Telephone call before visiti 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
 
 
Determine treatment failure 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
X 
X 
Occurrence of lumbar 
surgeryj 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
Collect remaining rescue 
medication 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X = Essential examination. 
CGIC = Clinical Global Impression of Change; DC = Discontinuation; EQ-5D-5L = EuroQol Group 5-Dimension Quality of Life 
instrument, 5-level version; LDH = Lumbar Disc Herniation; MRI = Magnetic Resonance Imaging; ODI = Oswestry Disability Index; PGIC 
= Patient Global Impression of Change; SF-36 = 36-Item Short-Form Health Survey; VAS = Visual Analogue Scale; WPAI = Work 
Productivity and Activity Impairment Questionnaire. 
 
 


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a Laboratory tests are provided as listed in Table 2. 
b Women of childbearing potential only. Blood test will be performed at Visit 1, and urine 
test will be performed at Visit 2. 
c If subject is re-screened, the imaging is not required to be repeated as long as the imaging 
was performed within 28 days prior to the re-screening informed consent (Visit 1) date or 
within 56 days of the planned randomization date, whichever is longer.  
d If repeat imaging is needed during follow-up visits, the window for imaging will be 
extended by a maximum of an additional 7 days. 
e Subjects will be educated on appropriate expectations around their participation in a clinical 
study and the importance of reliably, consistently and accurately reporting their pain 
throughout the study. 
f If a subject has enough remaining acetaminophen (rescue medication 1) or 
hydrocodone/acetaminophen (rescue medication 2), additional medication will not be 
provided. Not to exceed a maximum of 60 tablets of hydrocodone/acetaminophen throughout 
the study. 
g Subjects may be randomized on the day before (Day -1) or the day of (Day 1) 
investigational product administration. 
h Treatment should be administered within 4 weeks after informed consent. 
i Site staff should contact a subject by telephone call and/or other method by a minimum of 
14 days before scheduled visit. 
j Subjects who discontinued the study will be followed until the Week 52 Visit. 
k Before each subject is screened for the study, a pre-screen informed consent can be 
obtained from the subject for the purpose of conducting a detailed assessment of subject 
eligibility on an as-needed basis. Investigator can conduct pre-screening for procedures and 
assessments considered necessary for the subject’s eligibility assessment (e.g., neurological 
examination, pain assessment, imaging assessment) and these procedures and assessments 
can be set based on the investigator’s decision. 
l Urine drug tests at these visits are required only for subjects receiving 
hydrocodone/acetaminophen rescue. 


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9.2 
Procedures by Visit 
Each subject will be asked to complete 10 study visits: 
 Screening period (Visit 1) 
 Randomization at Week 0, Day -1 or Day 1 (Visit 2) 
 Investigational product treatment at Week 0, Day 1 (Visit 2) 
 Follow-up visits at Week 1, Week 2, Week 4, Week 6, Week 13, Week 26, Week 39, 
and Week 52 (Visit 3 through Visit 10) 
Subjects who discontinued the study in mid-course will be asked to complete a 
discontinuation visit. Before each subject is screened for the study, a pre-screen informed 
consent can be obtained from the subject for the purpose of conducting a detailed assessment 
of subject eligibility on an as-needed basis. 
9.2.1 Visit 1: Screening Period (Day -28 to Day -1) 
The following activities will be performed at screening (Visit 1) or during the screening 
period (Day -28 to -1). 
Before performing any screening procedures: 
 Obtain written informed consent. 
After informed consent obtained: 
 Collect demographics and baseline characteristics, including diagnosis and history of 
LDH. 
 Collect medical history. 
 Collect concomitant medication and therapy information, including for the treatment 
of LDH. 
 Collect vital signs. 
 Record baseline signs and symptoms as baseline conditions to assess future potential 
AEs. 
 Perform neurological examination. 
 Perform urine drug test. 
 Collect blood sample for laboratory tests (hepatitis test; pregnancy test [for women of 
childbearing potential]; hematology, hepatic, serology and chemistry panels; and 
blood alcohol test). 


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 Collect concomitant medication and therapy information.  
- 
Confirm use and amount of concomitant medication(s)/therapy(ies).  
- 
Assess use of restricted medication(s)/therapy(ies) for LDH.  
- 
Assess washout of prohibited medication(s)/therapy(ies) (washout of 
prohibited medication(s)/therapy(ies) to be completed before subject performs 
7 days of VAS assessment).  
 Perform imaging tests (X-ray and MRI), assess the images, and transmit the images to 
the central independent image readers for assessment of eligibility. 
At least by 14 days prior to randomization date, sites should: 
 Provide instructions for recording daily pain assessment and rescue medication use. 
 Provide subject education and materials on accurate pain reporting and appropriate 
expectations of personal benefit in a clinical trial. 
 Distribute subject daily diary. 
 Distribute acetaminophen as a rescue medication. 
After subject performs 7 days of VAS assessment: 
 Record AEs. 
 Verify conformance with inclusion/exclusion criteria. 
9.2.2 Visit 2: Randomization (Day -1 or Day 1) 
The following activities will be performed on the day before (Day -1) or the day of (Day 1) 
investigational product administration. 
Before randomization: 
 Complete the ODI, SF-36, EQ-5D-5L, and WPAI assessments. 
 Collect concomitant medication and therapy information.  
- 
Confirm use and amount of concomitant medication(s)/therapy(ies).  
- 
Assess use of restricted medication(s)/therapy(ies) for LDH.  
- 
Confirm washout of prohibited medications. 
- 
Confirm rescue medication use. 
 Collect vital signs. 
 Record AEs. 
 Perform neurological examination. 


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 Perform urine drug test. 
 Perform urine pregnancy test (for women of childbearing potential). 
 Confirm that the subject meets all of the inclusion criteria and none of the exclusion 
criteria and is therefore eligible to participate in the study. 
Randomization: 
Randomization must occur within screening period or on the day of investigational product 
administration (Day 1). 
 Randomize subject to SI-6603 or sham injection once all screening assessments are 
complete. 
9.2.3 Visit 2: Investigational Product Treatment (Day 1) 
The following activities will be performed at Visit 2 (Day 1). 
Before investigational product administration: 
 Monitor vital signs. 
 Record AEs, if randomization was performed on Day -1. 
During and after investigational product administration: 
The following activities will be performed by an unblinded site staff: 
 Administer SI-6603 or sham injection as described in Section 6.4. 
 Take and store the views of the target level with the needle placed within the disc or 
on the periphery. 
 Record concomitant medication and therapy information at investigational product 
administration. 
 Record AEs. 
After investigational product administration: 
Require subjects to rest for at least 4 hours. During this resting period, the investigator will 
monitor the subject’s vital signs and general health status. After subject monitoring, the 
investigator will judge if the subject is ready for discharge based on observation and 
verification there are no findings that negatively influence discharging the subject. 
 Monitor vital signs (approximately 2 and 4 hours after investigational product 
administration) and general health status. 
 Record AEs that occurred after investigational product administration. 


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 Record concomitant medication and therapy information following investigational 
product administration. 
 Provide instructions for recording daily pain assessment and rescue medication use. 
 Provide subject education on accurate pain reporting and appropriate expectations of  
personal benefit in a clinical trial. 
 Distribute acetaminophen rescue, as described in Section 6.6.4. 
 As applicable per Section 6.6.4, distribute hydrocodone/acetaminophen rescue 
medication. 
 Provide instructions to avoid any strenuous activities. 
9.2.4 Visit 3: Week 1 (Day 8 ±1 day) 
The following activities will be performed at Visit 3 (Week 1). 
 Complete ODI assessment. 
 Collect concomitant medication and therapy information.  
- 
Confirm use and amount of concomitant medication(s)/therapy(ies).  
- 
Assess use of restricted medication(s)/therapy(ies) for LDH.  
 Review the subject daily diary and assess compliance. 
 Collect vital signs. 
 Record AEs. 
 Perform neurological examination. 
 Perform urine drug test for subjects prescribed hydrocodone/acetaminophen rescue. 
 Collect blood sample for laboratory tests (hematology and chemistry panels). 
 Provide instructions for recording daily pain assessment and rescue medication use. 
 Distribute acetaminophen rescue, as described in Section 6.6.4. 
 As applicable per Section 6.6.4, distribute hydrocodone/acetaminophen rescue 
medication. Discuss usage and counsel, as appropriate. 
 Remind subject to avoid any strenuous activities. 
9.2.5 Visits 4 and 5: Week 2 (Day 15 ±3 days) and Week 4 (Day 29 ±3 days) 
The following activities will be performed at Visit 4 (Week 2) and Visit 5 (Week 4): 
 Complete the ODI, SF-36, and PGIC assessments (SF-36 will not be performed at 
Visit 4). 
 Collect concomitant medication and therapy information.  


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- 
Confirm use and amount of concomitant medication(s)/therapy(ies).  
- 
Assess use of restricted medication(s)/therapy(ies) for LDH.  
 Collect vital signs. 
 Record AEs. 
 Perform neurological examination. 
 Perform urine drug test for subjects prescribed hydrocodone/acetaminophen rescue. 
 Complete the CGIC assessment. 
 Provide instructions for recording daily pain assessment and rescue medication use. 
 Distribute acetaminophen rescue, as described in Section 6.6.4. 
 As applicable per Section 6.6.4, distribute hydrocodone/acetaminophen rescue 
medication. Discuss usage and counsel, as appropriate. 
 Remind subject to avoid any strenuous activities. 
9.2.6 
Visit 6: Week 6 (Day 43 ±7 days) 
The following activities will be performed at Visit 6 (Week 6): 
 Complete the ODI, SF-36, and PGIC assessments. 
 Collect concomitant medication and therapy information.  
- 
Confirm use and amount of concomitant medication(s)/therapy(ies).  
- 
Assess use of restricted medication(s)/therapy(ies) for LDH.  
 Collect vital signs. 
 Record AEs. 
 Perform neurological examination. 
 Perform urine drug test for subjects prescribed hydrocodone/acetaminophen rescue. 
 Complete the CGIC assessment. 
 Collect blood sample for laboratory tests (hematology and chemistry panels).  
 Provide instructions for recording daily pain assessment and rescue medication use. 
 Provide subject education on accurate pain reporting and appropriate expectations of 
personal benefit in a clinical trial. 
 Distribute acetaminophen rescue, as described in Section 6.6.4. 
 As applicable per Section 6.6.4, distribute hydrocodone/acetaminophen rescue 
medication. Discuss usage and counsel, as appropriate. 
 Remind subject to avoid any strenuous activities. 


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9.2.7 Visit 7: Week 13 (Day 92 -7, +14 days) 
Contact will be made with the subject by telephone call (and/or other method) by a minimum 
of 14 days before this visit. The following activities will be performed at Visit 7 (Week 13): 
 Complete the ODI, SF-36, PGIC, EQ-5D-5L, and WPAI assessments. 
 Collect concomitant medication and therapy information.  
- 
Confirm use and amount of concomitant medication(s)/therapy(ies).  
- 
Assess use of restricted medication(s)/therapy(ies) for LDH.  
 Collect vital signs. 
 Record AEs. 
 Perform neurological examination.  
 Perform urine drug test for subjects prescribed hydrocodone/acetaminophen rescue. 
 Complete the CGIC assessment. 
 Collect blood sample for laboratory tests (hematology and chemistry panels). 
 Determine whether there is treatment failure. 
 Provide instructions for recording daily pain assessment and rescue medication use. 
 Distribute acetaminophen rescue, as described in Section 6.6.4. 
 As applicable per Section 6.6.4, distribute hydrocodone/acetaminophen rescue 
medication. Discuss usage and counsel, as appropriate. 
 Remind subject to avoid any strenuous activities. 
 Perform imaging tests (X-ray and MRI)*, assess the images, and transmit the images 
to the central independent image readers. 
* If repeat imaging is needed, the window for imaging only will be extended by a 
maximum of an additional 7 days. 
9.2.8 Visit 8: Week 26 (Day 183 ±14 days) 
Contact will be made with the subject by telephone call (and/or other ways) by a minimum of 
14 days before these visits. The following activities will be performed at Visit 8 (Week 26): 
 Complete the ODI, SF-36, and PGIC assessments. 
 Collect concomitant medication and therapy information.  
- 
Confirm use and amount of concomitant medication(s)/therapy(ies).  
- 
Assess use of restricted medication(s)/therapy(ies) for LDH.  
 Collect vital signs. 


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 Record AEs. 
 Perform neurological examination. 
 Perform urine drug test for subjects prescribed hydrocodone/acetaminophen rescue. 
 Complete the CGIC assessment. 
 Provide instructions recording daily pain assessment and rescue medication use. 
 Distribute acetaminophen rescue, as described in Section 6.6.4. 
 As applicable per Section 6.6.4, distribute hydrocodone/acetaminophen rescue 
medication. Discuss usage and counsel, as appropriate. 
 Remind subject to avoid any strenuous activities. 
9.2.9 Visit 9: Week 39 (Day 274 ±14 days) 
Contact will be made with the subject by telephone call (and/or other ways) by a minimum of 
14 days before these visits. The following activities will be performed at Visit 9 (Week 39): 
 Complete the ODI, SF-36, and PGIC assessments. 
 Collect concomitant medication and therapy information.  
- 
Confirm use and amount of concomitant medication(s)/therapy(ies).  
- 
Assess use of restricted medication(s)/therapy(ies) for LDH.  
 Collect vital signs. 
 Record AEs. 
 Perform neurological examination. 
 Perform urine drug test for subjects prescribed hydrocodone/acetaminophen rescue. 
 Complete the CGIC assessment. 
 Provide instructions recording daily pain assessment and rescue medication use. 
 Provide subject education on accurate pain reporting and appropriate expectations of 
personal benefit in a clinical trial. 
 Distribute acetaminophen rescue, as described in Section 6.6.4. 
 As applicable per Section 6.6.4, distribute hydrocodone/acetaminophen rescue 
medication. Discuss usage and counsel, as appropriate. 
 Remind subject to avoid any strenuous activities. 
9.2.10 Visit 10: Week 52 (Day 365 ±14 days) 
Contact will be made with the subject by telephone call (and/or other ways) by a minimum of 
14 days before these visits. The following activities will be performed at Visit 10 (Week 52): 


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 Complete the ODI, SF-36, PGIC, EQ-5D-5L, and WPAI assessments 
 Collect concomitant medication and therapy information.  
- 
Confirm use and amount of concomitant medication(s)/therapy(ies).  
- 
Assess use of restricted medication(s)/therapy(ies) for LDH.  
 Collect vital signs. 
 Record AEs. 
 Record occurrence of any lumbar surgery. 
 Perform neurological examination. 
 Complete the CGIC assessment. 
 Determine whether there is treatment failure. 
 Collect or account for any remaining rescue medication. 
 Perform imaging tests (X-ray and MRI) *, assess the images, and transmit the images 
to the central independent image readers. 
* If repeat imaging is needed, the window for imaging will be extended by a 
maximum of an additional 7 days. 
9.2.11 Discontinuation Visit  
Subjects who discontinue early from the study will be asked to complete a discontinuation 
visit. The following activities will be performed at the discontinuation visit: 
 Complete the ODI, SF-36, PGIC, EQ-5D-5L, and WPAI assessments  
 Collect concomitant medication and therapy information.  
- 
Confirm use and amount of concomitant medication(s)/therapy(ies).  
- 
Assess use of restricted medication(s)/therapy(ies) for LDH.  
 Collect vital signs. 
 Record AEs. 
 Record occurrence of any lumbar surgery. 
 Perform neurological examination. 
 Complete the CGIC assessment. 
 Collect blood sample for laboratory tests (blood for hematology and chemistry 
panels)*. 
 Determine whether there is treatment failure. 
 Collect or account for any remaining rescue medication. 


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 Perform imaging tests (X-ray and MRI), assess the images, and transmit the images to 
the central independent image readers 
* If the subject discontinues prior to or within Week 13. 
Subjects who discontinue early from the study will also be followed until Week 52 for the 
occurrence of any lumbar surgery. 
9.2.12 Unscheduled Visit 
In the event the investigator needs to conduct follow-up assessments to evaluate an AE, the 
following safety assessments may be performed on an unscheduled basis: 
 Collect vital signs. 
 Collect blood sample for laboratory tests (hematology and chemistry panels). 
 Perform imaging tests (X-ray and MRI), assess the images, and transmit the images to 
the central independent image readers. 
9.3 
Background and Demographic Characteristics 
9.3.1 Demographics 
For subject demographics, the following information will be documented at the screening 
visit. 
 Date of birth 
 Sex [Male, Female] 
 Race [American Indian or Alaska Native, Asian, Black or African American, Native 
Hawaiian or Other Pacific Islander, White, Other] 
 Ethnicity [Hispanic or Latino, Not Hispanic or Latino] 
 Height 
 Weight 
 Smoking history [Never smoked, Past smoker, Current smoker] 
 Occupation [Heavy labor, Light labor] 
9.3.2 History of Lumbar Disc Herniation 
For disease history of LDH, the following information will be documented at the screening 
visit. 
 Date of Diagnosis 
 Herniation Site [L4-L5, L5-S1*] 
 Location of Herniation [Left, Right] 


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 Location of Radicular Leg Pain [Left, Right] 
 Date of Onset of Current Radicular Leg Pain 
 Ongoing Low Back Pain Caused by Herniation [Yes, No] 
*including L5-L6 
9.3.3 Medical History 
For the documentation of 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 investigated at the screening visit. The medical history will be obtained by 
interviewing the subject and/or by inspecting his/her medical records. 
A brief history of the following treatments, if they have been used, will be recorded: 
 Medications used for LDH in the 26 weeks before the time of informed consent: 
Name of medication, Usage, Frequency, Route, Start date, End date 
 Physical therapies used for LDH in the 26 weeks before the time of informed consent: 
Name of therapy, Frequency, Start date, End date 
 Block procedure used for LDH: Name of procedure, Date 
9.4 
Concomitant Medications/Therapies 
9.4.1 Concomitant Medications 
Investigators will record the following information for all medications used concomitantly 
during the period from 6 weeks prior to informed consent to 52 weeks after administration, or 
until the time of discontinuation. 
 Name of medication 
 Dose 
 Route of administration 
 Frequency 
 Start date / End date 
 Indication [LDH, Adverse event, Medical history, Other] 
9.4.2 Concomitant Therapies 
Investigators will record the following information for therapies used concomitantly for 
treatment of LDH during the period from time of informed consent to 52 weeks after 
administration, or until the time of discontinuation. 
 Name of therapy 


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 Frequency 
 Start date / End date 
9.5 
Efficacy Assessments 
9.5.1 Pain Intensity 
 Assessment Points:  Daily from screening until Week 52 
 Item:  Worst leg pain and worst low back pain during the past 24 hours assessed by 
100 mm VAS 
 Method:  The 100 mm VAS pain assessment tool will be used to measure pain 
intensity. At the screening visit, the investigator will provide a daily diary and instruct 
subjects to record daily the pain intensity from LDH over the last 24 hours basically 
before going to bed.   
9.5.2 Oswestry Disability Index 
 Assessment Points:  Week 0, 1, 2, 4, 6, 13, 26, 39, and 52, and discontinuation visit 
 Item:  ODI, Version 2.1a 
 Method:  Investigator will have subjects answer the ODI questionnaire at each listed 
visit. 
9.5.3 36-item Short Form Survey 
 Assessment Points:  Week 0, 4, 6, 13, 26, 39, and 52, and discontinuation visit 
 Item:  SF-36 v2 Standard, US Version 2.0 
 Method:  Investigator will have subjects answer the SF-36 questionnaire at each 
listed visit. 
9.5.4 EuroQol Group 5-Dimension Quality of Life Instrument 
 Assessment Points:  Week 0, 13, and 52, and discontinuation visit 
 Item:  EQ-5D-5L 
 Method:  Investigators will have subjects answer the EQ-5D-5L questionnaire at 
each listed visit. 
9.5.5 Patient Global Impression of Change 
 Assessment Points:  Week 2, 4, 6, 13, 26, 39, and 52, and discontinuation visit 
 Item:  PGIC questionnaire 


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 Method:  Investigators will have subjects answer the PGIC questionnaire at each 
listed visit. 
9.5.6 Clinical Global Impression of Change 
 Assessment Points:  Week 2, 4, 6, 13, 26, 39, and 52, and discontinuation visit 
 Item:  CGIC questionnaire 
 Method:  Investigators will answer the CGIC questionnaire based on subject's 
condition at each listed visit. 
9.5.7 Work Productivity and Activity Impairment 
 Assessment Points:  Week 0, 13, and 52, and discontinuation visit 
 Item:  Work Productivity and Activity Impairment Questionnaire: Pain related to 
Lumbo-sacral Radiculopathy V1.0 (WPAI-PLR, referred to as WPAI) 
 Method:  Investigators will have subjects answer the WPAI questionnaire at each 
listed visit. 
9.5.8 Rescue Medication Use 
 Assessment Points:  Daily from screening until Week 52 
 Item:  Amount of rescue medication used 
 Method:  At the screening visit, the investigator will provide a daily diary and 
instruct subjects to record daily the amount of rescue medication over the last 24 
hours, basically before going to bed. The investigator will clarify the requirements for 
timing of opioid rescue as it relates to the other study assessments. 
9.5.9 Neurologic Status 
 Assessment Points:  All Visits 
 Item:  SLR test [Positive (≤70°) or Negative (>70°)], sensation [Yes, No for 
existence of hypoesthesia], muscle strength [Yes, No for existence of muscle 
weakness], and deep tendon reflex [Yes, No for existence of hyporeflexia] 
 Method:  Neurological examinations will be performed by the investigator, and the 
results will be documented. 
9.5.10 Treatment Failure 
 Assessment Points:  Week 13 and 52, and discontinuation visit 


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 Item:  Treatment Failure [Yes, No], Reason [Concomitant medication use, Safety 
reason, Efficacy reason, Poor response, Increase of vertebral body angle, Increase of 
vertebral body translation] 
 Method:  Investigator will record the condition of and information about treatment 
failure. Treatment failure is defined in Section 8.1.3.  
9.5.11 Disc and Herniation Volumes 
 Assessment Points:  Screening visit, Week 13, and 52, and discontinuation visit 
 Item:  Disc volume, Herniation volume 
 Method:  Disc and herniation volumes will be assessed with MRI by a central 
imaging facility. The investigator or site staff will collect the images and transmit 
them to the central imaging facility, according to a separately distributed manual. 
9.5.12 Post-treatment Surgery for Lumbar Disc Herniation at Target Level 
 Assessment Point:  Week 52 (subjects who discontinued the study will be also 
followed until 52 weeks after injection) 
 Item:  Occurrence of lumbar disc surgery for LDH [Yes, No], Date of surgery 
 Method:  At 52 weeks after injection, investigators will collect information on the 
occurrence of post-treatment surgery for treatment of LDH at the same level of 
administration of the investigational product, including for subjects who discontinued 
from the study. 
9.6 
Safety Assessments 
9.6.1 Adverse Events 
Investigators should investigate any AEs occurring after the time of informed consent as 
follows and record them in the eCRF. Questions should be nonspecific, such as “How have 
you been feeling since the last visit?” 
 AE Term 
 Period AE occurred [Prior to injection, After injection] 
 Start date 
 End date 
 Outcome [Recovered/Resolved, Recovering/Resolving, Not recovered/Not resolved, 
Recovered/Resolved with sequelae, Fatal, Unknown] 
 Severity [Mild, Moderate, Severe] 
 Causality [Related, Not related] 


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 Action Taken [None, Medication, Other] 
 AE that caused study discontinuation [No, Yes] 
 Serious Event [No, Yes] 
 Special Interest [No, Yes] 
9.6.2 Laboratory Tests 
 Assessment Points for All Subjects:  Screening visit, Weeks 0, 1, 6, and 13, and 
discontinuation visit prior to or within Week 13 
 Additional Assessment Points for Subjects Receiving Hydrocodone/Acetaminophen 
Rescue: Week 1, 2, 4, 6, 13, 26 and 39 
 Items:  
- 
Screening visit – urine drug test, serum pregnancy test, blood alcohol test, and 
hematology, serology markers, hepatic, and chemistry panels. 
- 
Week 0 – urine drug test, urine pregnancy test. 
- 
Week 1, Week 6, Week 13 and discontinuation visit (prior to or within Week 
13) – hematology and chemistry panels 
- 
Week 1, 2, 4, 6, 13, 26 and 39 – urine drug test (only for subjects receiving 
hydrocodone/acetaminophen rescue) 
 Method:  Urine assessments will be performed at the study sites with provided kits.  
Blood assessments will be performed by a central laboratory. The investigator or site 
staff will collect blood samples according to a separately distributed manual. 
Laboratory variables from blood tests will be determined as listed in Table 2.  
 
 
 


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Table 2  
Laboratory Assessments 
Hematology: 
hematocrit  
hemoglobin 
platelets  
red blood cell count 
white blood cell count with differential
Clinical chemistry: 
creatinine 
C-reactive protein 
total protein 
total bilirubin 
direct bilirubin (determined if total bilirubin is elevated) 
total cholesterol 
urea nitrogen 
uric acid
Electrolytes: 
calcium 
chloride 
magnesium 
potassium 
sodium 
Liver enzymes: 
alkaline phosphatase 
AST 
ALT 
lactic dehydrogenase 
-glutamyl transpeptidase 
albumin
Serological markers (at screening 
only) 
Hepatitis B surface antigen 
Hepatitis C antibody; hepatitis C RNA only when required for 
documentation of sustained virologic response to reported 
effective treatment. 
HIV
AST = aspartate aminotransferase; ALT = alanine aminotransferase; HIV = human immunodeficiency virus 
 
 


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9.6.3 Vital Signs 
 Assessment Points:  All visits 
 Items: 
- Blood pressure (systolic and diastolic; mmHg)  
- Heart rate (beats per minute) 
- Body temperature (°F or °C) - any route, but consistent for an individual subject 
- Respiration rate (breaths per minute) 
 Method:  Vital signs will be performed at study site. 
9.6.4 Assessments by X-ray and MR Images 
 Assessment Points:  Screening visit, Week 13, 52, and discontinuation visit 
 Item:  Disc height (disc index), Vertebral body translation, Vertebral body angle 
formed by flexion, Modic classification 
 Method:  Imaging assessments of X-ray and MR images will be performed by a 
central imaging facility. The investigator or site staff will collect images and transmit 
them to the central imaging facility according to a separately distributed manual. 
9.6.5 Post-treatment Surgery for LDH at Non-target Level 
 Assessment Point:  Week 52 (subjects who discontinued the study will also be 
followed until 52 weeks after injection) 
 Item:  Occurrence of lumbar disc surgery [Yes, No], Date of surgery, Target segment 
 Method:  At 52 weeks after injection, investigators will collect information on the 
occurrence of post-treatment lumbar disc surgery at levels other than where 
investigational product was administered, including for subjects who discontinued 
from the study. 
9.6.6 Post-treatment Lumbar Surgery Not for LDH 
 Assessment Point:  Week 52 (subjects who discontinued the study will also be 
followed until 52 weeks after injection) 
 Item:  Occurrence of lumbar surgery [Yes, No], Date of surgery, Indication, Target 
segment, Surgical procedure 
 Method:  At 52 weeks after injection, investigators will collect information on the 
occurrence of post-treatment lumbar surgery not for LDH, including for subjects who 
discontinued from the study. 
 


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9.7 
Other Assessments 
9.7.1 Pregnancy Test 
The sponsor has a responsibility to monitor the outcome of pregnancies where there has been 
maternal exposure to an investigational product.  
Pregnancy alone is not regarded as an AE unless there is a suspicion that the investigational 
product 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. Hospitalization for normal delivery of a healthy newborn should not be 
considered a serious adverse event (SAE). 
All pregnancies must be reported by the investigator via the eCRF. The investigator must 
follow up and document the course and outcome of all pregnancies, even if the subject was 
discontinued from the study or if the study has finished. Any SAE that occurs during 
pregnancy (e.g., serious maternal complications, spontaneous or therapeutic abortion, ectopic 
pregnancy, stillbirth, neonatal death, congenital anomaly, or birth defect) must be reported 
within 24 hours in accordance with the procedure for reporting SAEs. 
If a female partner of a male study subject who has been exposed to the investigational 
product becomes pregnant before the end of Week 13, the pregnancy and outcome of 
pregnancy should be monitored in the same fashion. 
9.8 
Subject Education 
9.8.1 Accurate Pain Reporting Training 
The Accurate Pain Reporting Program (“Reporting Your Pain,” 
,
Wayland, MA) consists of a set of subject and staff educational materials and instructions on 
how to accurately and reliably report pain scores and on the proper use of pain intensity 
scales, with the aim of increasing subjects’ pain reporting accuracy. Staff training will be 
completed prior to performing any subject assessments. Subjects receive training at the 
screening visit. 
9.8.2 Appropriate Expectations Training 
The training “Participating in a Research Study, What you need to know” (
, Wayland, MA) consists of a set of subject and staff educational materials for
training on appropriate expectations of personal benefit while participating in a clinical trial. 
The purpose is to provide subjects with truthful information that will neutralize the typically 
excessive expectations that drive high placebo responses in clinical trials. Subjects receive 
initial training at the screening visit.


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10 ADVERSE EVENTS 
10.1 Definitions 
10.1.1 Adverse Events 
An AE is any untoward medical occurrence that occurs in a subject administered a 
investigational product, and that does not necessarily have to have a causal relationship with 
the treatment. An AE can therefore be any unfavorable and unintended sign (including 
abnormal laboratory findings and the imaging findings listed below), 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 
 Changes of vertebral body endplates and adjacent bone marrow as visible by MRI. 
The criteria are as follows: Modic Type 1, Type 2, or Type 3 change in vertebral body 
endplates and adjacent bone marrow. 
Note: The above events are limited to the targeted level of the procedure and the adjacent 
vertebral bodies. 
All AEs, including concurrent illnesses, occurring during the study will be documented in the 
subject source record and eCRF. Concomitant illnesses that existed before entry into the 
study will not be considered AEs unless they worsen after the investigational product 
administration. All AEs, regardless of the source of identification (e.g., physical examination, 
laboratory assessments, imaging findings, subject reports) must be documented. 
Pre-existing conditions will be recorded in the subject source record and eCRF on the 
Medical History or appropriate page.  
A TEAE will be defined as an AE that begins or that worsens in severity after the 
investigational product has been administered. 
All AEs will be coded using Medical Dictionary for Regulatory Activities (MedDRA) 
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10.1.2 Serious Adverse Events 
An SAE is defined as any untoward medical occurrence at any dose that: 
 Results in death; 
 Is life-threatening, meaning that the subject 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; 
 Results in a congenital anomaly or birth defect; or 
 Is an important medical event(s) that may not be immediately life-threatening or result 
in death or hospitalization but that may jeopardize the subject 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. 
AEs reported from clinical studies and associated with hospitalization or prolonged 
hospitalization are considered serious. Any hospitalization except observational admissions 
of less than 24 hours for logistical reasons meets these criteria. This category also includes 
transfer within the hospital to an acute/intensive care unit (e.g., from a standard-of-care unit 
to an acute/intensive care unit). 
Hospitalization does not include the following: 
 Rehabilitation facilities, hospice facilities, or respite care (e.g., caregiver relief); 
 Nursing homes or skilled nursing facilities; 
 Emergency room visits; 
 Same-day surgeries (such as outpatient/same day/ambulatory procedures); or 
 <24-hour admissions for observation or evaluation for logistical reasons. 
Hospitalization or prolongation of hospitalization in the absence of a precipitating, clinical 
AE is not in itself an SAE. Examples include the following: 
 Admission for treatment of a preexisting condition that did not worsen; 


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 Hospitalizations for cosmetic elective surgery, social, and/or convenience admissions; 
or 
 Pre-planned treatments or surgical procedures, which should be noted in the baseline 
documentation for the individual subject. 
10.1.3 Vital Signs and Laboratory Tests 
If an abnormal laboratory finding or vital sign is observed, the investigator should judge 
whether it is an AE or not by referring to the following criteria: 
 When any medical intervention such as pharmacotherapy or surgical care is 
performed in order to improve the abnormality, or 
 Other than case above, when investigator judges that the abnormality is medically 
important and should be considered an AE. 
10.1.4 Anaphylaxis 
All AEs that meet the definition of anaphylaxis published by the National Institute of Allergy 
and Infectious Disease Food Allergy and Anaphylaxis Network (NIAID/FAAN) should be 
reported as SAEs throughout the study.(13) 
Table 3  
Clinical Criteria for Diagnosing Anaphylaxis 
Anaphylaxis is highly likely when any one of the following 3 criteria are fulfilled:
- 
Acute onset of an illness (minutes to several hours) with involvement of the skin, mucosal tissue, 
or both (e.g., generalized hives, pruritus or flushing, swollen lips-tongue-uvula) 
AND AT LEAST ONE OF THE FOLLOWING 
a. 
Respiratory compromise (e.g., dyspnea, wheeze-bronchospasm, stridor, reduced PEF, 
hypoxemia) 
b. 
Reduced BP or associated symptoms of end-organ dysfunction (e.g., hypotonia [collapse], 
syncope, incontinence) 
- 
Two or more of the following that occur rapidly after exposure to a likely allergen for that patient 
(minutes to several hours): 
a. Involvement of the skin-mucosal tissue (e.g., generalized hives, itch-flush, swollen lips-
tongue-uvula) 
b. Respiratory compromise (e.g., dyspnea, wheeze-bronchospasm, stridor, reduced PEF, 
hypoxemia) 
c. Reduced BP or associated symptoms (e.g., hypotonia [collapse], syncope, incontinence) 
d. Persistent gastrointestinal symptoms (e.g., crampy abdominal pain, vomiting) 
- 
Reduced BP after exposure to known allergen for that patient (minutes to several hours): 
a. Systolic BP of less than 90 mm Hg or greater than 30% decrease from that person’s baseline
PEF = Peak expiratory flow; BP = Blood pressure 
10.1.5 Adverse Events of Special Interest 
For this study, the following events will be captured as Adverse Events of Special Interest 
(AESI) and recorded in the eCRF: 
 Injection at wrong disc level 


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 Discitis 
 Osteomyelitis 
 Hematomas 
 Hypersensitivity 
 Imaging findings (See Section 10.1.1 for details) 
- Disc height (disc index) 
- Vertebral body translation 
- Vertebral body angle formed by flexion 
- New Modic change 
 Leg pain* 
 Back pain* 
*Defined as symptoms: 
- 
associated with primary disease; 
- 
caused by injection of investigational drug; or 
- 
related to injection procedure. 
10.2 Assessment of Adverse Events 
It is the responsibility of the investigator to collect all AEs, both serious and nonserious, 
derived by spontaneous, unsolicited reports of subjects, by observation, and by routine open 
questioning (e.g., "How have you felt since I last saw you?"). 
Adverse event recording will extend from the signing of the ICF until the AE resolves or 
stabilizes. If AEs are ongoing at the time of the last study visit, only treatment-related AEs 
will be followed beyond 12 months after investigational product administration. All AEs, 
regardless of the relationship to investigational product, will be recorded in the subject source 
record and eCRF. 
All AE reports should contain a brief description of the event, date of onset, date of 
resolution, intensity, treatment required, timing and relationship to investigational product, 
action taken with the investigational product, outcome, and whether the event is classified as 
serious. 
10.2.1 Intensity 
The intensity of each AE must be assessed by the investigator using one of the following 
categories and recorded in the eCRF: 


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 Mild:  No particular interference with the subject’s activities of daily living or, 
despite slight interference, no particular intervention indicated (Common 
Terminology Criteria for Adverse Events [CTCAE] Grade 1) 
 Moderate:  Interference with the subject’s activities of daily living and minimal 
intervention indicated (CTCAE Grade 2) 
 Severe:  Disabling and almost complete interference with the subject’s activities of 
daily living or systemic intervention indicated (CTCAE Grade 3/4) 
10.2.2 Causality 
The investigator will assess the causality/relationship between the investigational product and 
the AE and record the assessment in the eCRF. Causality will be recorded 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 in the eCRF with details of the concomitant 
disease or medication or other cause. 
The causal relationship of the AE to investigational product will be described as: 
 Not related:  No temporal correlation or attributability to any other factor, such as 
the underlying disease, a complication, a concomitant drug, a predisposition, or 
concomitant intervention, can be explicitly explained. 
 Related: There is a reasonable possibility that the relevant event can be judged to be 
due to the investigational product or a causal relationship cannot be ruled out. 
10.3 Follow-up of Adverse Events 
During the study, all AEs experienced by a subject, 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 subject is lost to follow-up, or 
until there is a reasonable explanation for the need not to follow up. If an AE is ongoing at 
the time of the last study visit, only treatment-related AEs will be followed beyond 12 months 
after investigational product administration. 
10.4 Reporting Serious Adverse Events 
The investigator must report any SAEs within 24 hours of becoming aware of the event. 
Reporting guidance will be provided separately. 


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The investigator and the sponsor or designee will review each SAE report and the sponsor or 
designee will evaluate the seriousness and the causal relationship of the event to study 
treatment. In addition, the sponsor or designee will evaluate the expectedness according to 
the reference document. Based on the investigator’s and sponsor’s assessment of the event, a 
decision will be made concerning the need for further action. 
Serious adverse events occurring after the end of the study and coming to the attention of the 
investigator must be reported only if, in the opinion of the investigator, they are considered 
causally related to the investigational product. 
10.5 Action Taken for Adverse Events 
The investigator will treat participants experiencing AEs appropriately and observe them at 
suitable intervals until their symptoms resolve or their status stabilizes. If any medication is 
administered in response to the AE, this medication should be noted on the concomitant 
medication eCRF as a concomitant medication administered. The action taken and the 
outcome must be recorded. The term of AE resolution (e.g., Recovered/Resolved, Not 
recovered/Not resolved, Recovered/Resolved with sequelae, Recovering/Resolving, Fatal, 
Unknown) should also be recorded. 
10.6 Action Taken for Serious Adverse Events 
Serious adverse events will be recorded on the AE and SAE eCRFs. Sponsor or designee will 
provide safety reports to the Food and Drug Administration (FDA) and investigators in 
accordance with the regulations detailed in 21 Code of Federal Regulations (CFR) 312.32. 
11 STATISICAL METHODS 
The planned statistical analysis will be described in detail in a separately prepared statistical 
analysis plan (SAP). 
11.1 Analysis Populations 
The efficacy analyses will be performed on the modified intention-to-treat (mITT) 
population. Efficacy analyses of the per-protocol (PP) population will be supportive of the 
mITT analysis. The safety analyses will be performed on the safety population. 
11.2 Modified Intention-to-Treat Population 
The mITT population is defined as all randomized subjects who received the study injection, 
analyzed according to the assigned treatment. 


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11.3 Per Protocol Population 
The PP population is defined as all mITT subjects who had no major protocol deviations that 
could affect the primary efficacy assessment. The details of major protocol deviations will be 
defined in the SAP, and included subjects will be determined prior to unblinding. 
11.4 Safety Population 
The safety population is defined as all randomized subjects who received the study injection, 
analyzed according to the treatments subjects received. 
11.5 Demographics, Baseline Characteristics, Medical History, and Concomitant 
Medications 
Baseline demographic and background variables will be summarized by treatment group and 
overall. For categorical variables, frequencies and percentages will be presented. For 
continuous variables, descriptive statistics be presented, including sample size, mean, 
median, standard deviation, minimum, maximum, Q1, and Q3. 
11.6 Efficacy Analyses 
11.6.1 Primary 
The change from baseline in the worst leg pain scores will be analyzed by a mixed model for 
repeated measures (MMRM) analysis for Week 1 through Week 52 in the mITT population. 
The average worst leg pain scores over the previous 7 days will be analyzed at Week 1, 2, 4, 
6, 13, 26, 39, 52 (See Section 11.8.1 for additional details). The primary comparison will be 
the mean change from baseline of the SI-6603 group at Week 13 compared with the control 
group, estimated using this model. The model will include the baseline worst leg pain score, 
treatment, time, treatment-by-time interaction, and duration of leg pain as fixed effects. An 
unstructured covariance will be used to model the covariance structure among repeated 
measures. Should the model fail to converge with the type = UN option, a compound 
symmetry structure will be used. Kenward-Roger method will be used for computing the 
denominator degrees of freedom. The missing data will be implicitly handled via a mixed-
effect model, without explicit imputation. 
11.6.2 Key Secondary 
A longitudinal analysis model will be used as described in the primary efficacy analysis for 
the analyses of change from baseline in the herniation volume at Week 13, change from 
baseline in the worst leg pain score at Week 52, and change from baseline in the ODI at 
Week 13. The baseline value of each outcome will be included as a covariate in these models 
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volume is collected only at Week 13 and 52; ODI assessment shares the same time points as 
the primary. 
11.6.3 Other Secondary 
All endpoints, including the primary and key secondary endpoints, will be summarized by 
treatment group and by time point. The differences of other secondary endpoints between the 
SI-6603 and control groups will be analyzed at each time point as below. In addition, weekly 
pain intensity scores will be summarized by treatment group. 
 A similar longitudinal analysis model will be used as described in the primary 
efficacy analysis for the analysis of change from baseline in pain intensity scores, 
function scores, QOL scores, and volumes, by including the corresponding baseline 
value as the fixed effect instead of the baseline worst leg pain score. 
 Neurologic status as determined by neurological examinations will be analyzed with a 
logistic regression model. Baseline neurologic status and duration of leg pain will be 
included as covariates. 
 For the global assessments of PGIC score and CGIC score, responder analysis with 
the two best categories as “responder” will be analyzed with a logistic regression 
model. Baseline worst leg pain score and duration of leg pain will be included as 
covariates. 
 Scores on the WPAI will be analyzed with the analysis of covariance model including 
the baseline value and duration of leg pain as covariates. 
 The incidence of rescue medication use will be analyzed with Fisher’s exact test, and 
the amount of rescue medication use and usage of concomitant medications for LDH 
will be analyzed with the Wilcoxon rank sum test. 
 Cumulative distribution of percentage change from baseline in worst leg pain and 
ODI will be generated, and differences between the SI-6603 and control groups in the 
percentages of subjects experiencing a >30% and >50% improvement in worst leg 
pain score will be analyzed with Fisher’s exact test. 
 For the analysis of the percentages of responders by composite definition, differences 
between the SI-6603 and control groups in the percentages of positive responders will 
be analyzed with a logistic regression model. Baseline worst leg pain score and 
duration of leg pain will be included as covariates. 
 Time to post-treatment surgery for LDH will be evaluated by survival analysis using 
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11.7 Safety Analyses 
Treatment-emergent AEs will be defined as any AEs that were recorded during or following 
the investigational product injection. Significant TEAEs will include TEAEs that result in 
study discontinuation. 
The incidence and its exact 95% confidence intervals (CIs) will be calculated by treatment 
group for TEAEs, serious TEAEs, significant TEAEs, and Treatment-emergent Adverse 
Events of Special Interest (TEAESI). The incidences of TEAEs, serious TEAEs, significant 
TEAEs, and TEAESI will be tabulated according to system organ class and preferred term by 
treatment group. The incidences of TEAEs and TEAESI will be tabulated by severity or time 
of occurrence for each system organ class and preferred term. Treatment-related TEAEs will 
also be summarized separately. 
If a subject has more than 1 occurrence of the same AE, he/she will be counted only once 
within that preferred term in the summary tables. The most severe occurrence of an AE, as 
well as the most extreme relationship of the AE to the study procedures and investigational 
product, will be indicated in cases of multiple occurrences of the same AE. 
Vital signs, laboratory assessments, imaging findings, and occurrence of post-treatment 
lumbar surgery will be summarized by treatment group. In addition, association between 
imaging findings and clinical symptoms will be assessed. 
 
11.8 General Considerations 
11.8.1 Data Handling of Worst Leg Pain 
The mean worst leg pain score from 7 consecutive days prior to each visit (the day of the visit 
will not be included) will be used as the worst leg pain score for each time point, after 
excluding the worst leg pain score on any of the following days: 
 Days after prohibited concomitant therapies of lumbar operation, lumbar percutaneous 
nucleotomy, or lumbar intradiscal therapies occurred, and 
 Days before the previous visit (for example, the Week 2 visit may fall just 5 days after 
Week 1; thus, the days prior to the Week 1 visit will not be considered as eligible for 
inclusion in the 7-day Week 2 average). 
In addition, if less than 3 days of worst leg pain scores are available of the 7 consecutive days 
prior to a visit, the worst leg pain score will be handled as missing at the time point. 
For the separate analysis of the weekly pain scores throughout the study, an average of the 
scores every 7 days will be calculated regardless of the visit date. 


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11.8.2 Visit Window and Unscheduled Assessments 
All data collected during 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 (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 summaries of 
the data.  
11.8.3 Significance Level and Confidence Coefficient 
A two-sided 5% significance level for any hypothesis testing will be used, and the 
methodology for the adjustment of multiplicity is described in Section 11.8.5. A two-sided 
95% confidence coefficient will be used for interval estimation unless otherwise specified. 
11.8.4 Missing Data 
For the efficacy analyses based on repeated-measures models of continuous endpoints, 
missing data will be implicitly handled via a mixed-effect model, without explicit imputation.  
Inferences based on this approach are unbiased under the assumption of missing at random, 
which is a weaker and more generally true assumption than missing completely at random. 
For the primary efficacy analysis, sensitivity analysis based on multiple imputation methods 
that changes imputation methods by missing pattern such as discontinuations due to AEs, 
lack of efficacy, and other will be performed for the mITT population. 
For the analysis of percentages of positive responders by composite definition, subjects who 
discontinue the study because of AEs related to LDH or lack of efficacy and subsequently 
have missing efficacy data will be classified as non-responders.  
No replacement of any missing data will be made for the safety analyses. 
11.8.5 Adjustment for Multiplicity 
To control family-wise error rate for multiple tests of the primary and key secondary 
endpoints, the following Holm-based testing algorithm will be used. 
 The treatment effect on the primary endpoint will be evaluated at α = 0.05.  
 If the effect on the primary endpoint is significant, the treatment effect on the key 
secondary endpoints of herniation volume at Week 13 and worst leg pain score at 
Week 52 will be evaluated using the truncated Holm test at α = 0.05. The truncation 
parameter will be set to 0.8.(14) 
 If the effect on the key secondary endpoint of herniation volume at Week 13 is 
significant and/or the effect on the key secondary endpoint of worst leg pain score at 


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Week 52 is significant, the effect on the key secondary endpoint of ODI at Week 13 
will be evaluated at a level that depends on the number of significant endpoints in the 
preceding step. If the key secondary endpoints of herniation volume at Week 13 and 
worst leg pain score at Week 52 are both significant, this level will be given by 
α = 0.05; if only one of the two endpoints is significant, this level will be given by 
α = 0.005. 
11.8.6 Sample Size Determination 
It is planned to enroll approximately 320 subjects, 160 in the SI-6603 group and 160 in the 
control group. 
Sample size estimation is based on using the mean difference in the worst leg pain score 
change from baseline in the primary efficacy analysis. The following assumptions were made 
to compute the sample size: 
 The 2-sample t-test comparing the group means of the change from baseline was used. 
(The 2-sample t-test approximates the test of the null hypothesis based on the repeated 
measures model that will be used in the primary efficacy analysis.) 
 Treatment difference between SI-6603 and control groups of 12 mm 
 Common standard deviation (SD) of 30 mm 
 Dropout rate of 15% 
 Power of 90% 
 Two-sided significance level of 5% 
12 ETHICAL CONSIDERATION 
12.1 Good Clinical Practice Compliance 
The procedures set out in this study protocol are designed to ensure that the sponsor, 
investigators, and other study participants abide by the principles of the Good Clinical 
Practice (GCP) guidelines of the International Conference for Harmonisation (ICH). The 
study also will be carried out in keeping with local legal requirements.  
12.2 Institutional Review Board or Independent Ethics Committee Approval 
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, including 
regulatory authorities, investigators, and IRB(s). A significant safety issue is one that has a 
significant impact on the course of the clinical study or program (including the potential for 


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suspension of the development program or amendments to protocols) or warrants an 
immediate update of the ICF. 
12.3 Data Protection 
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 subjects must be maintained. Subjects will be identified on 
the eCRF and other documents submitted by their subject number, initials, and/or birth date, 
not by name. Documents not to be submitted that identify the subject (e.g., the signed ICF) 
must be maintained in confidence by the investigator. 
12.4 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 subjects 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 include, but are not limited to: 
• The discovery of an unexpected (e.g. AE other than AEs listed in Table 6.1. in the current 
edition of the investigator brochure), significant, or unacceptable risk to the subjects 
enrolled in the study 
• The occurrence of an AE considered at least possibly related to SI-6603, 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; 
b. Abnormal X-ray findings of instability, defined as vertebral body angle formed by 
flexion of ≥5° or vertebral body translation of ≥3 mm; or 
c. Abnormal X-ray or MRI findings which subjects exhibit correlating clinical 
symptoms posing safety concerns, leads the investigator to judge it necessary for 
the subject to have surgical intervention 
• Failure to enroll subjects at an acceptable rate 
• A decision on the part of the sponsor to suspend or discontinue development of the drug 
13 PROTOCOL ADHERENCE AND INVESTIGATOR AGREEMENT 
Before the start of the study, the study protocol and/or other relevant documents will be 
approved by the IRB or competent authority, in accordance with local legal requirements. 


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The sponsor must ensure that all ethical and legal requirements have been met before the first 
subject 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 approval prior to 
implementation (if appropriate). Following approval, the protocol amendment(s) will be 
submitted to the Investigational New Drug application under which the study is being 
conducted.  
Administrative changes (not affecting the subject 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. 
14 PROCEDURE FOR COMPLETION AND CORRECTION OF THE 
CASE REPORT FORM 
This study will use electronic data collection. Data obtained during this study should be 
entered in the eCRFs or collected by electronic subject diary promptly and correctly. All data 
entered into the eCRF should be accurate and attributable to the subject’s source documents. 
Measurements for which source documents are usually available include laboratory 
assessments, MRIs, and X-rays. Some patient-reported outcomes will be completed on 
electronic devices by subjects and be stored in a database. These entries should not be 
changed by anyone except by the individual subject. 
Data from external sources, such as laboratory data, MRIs, and X-rays, will be processed 
outside the clinical database according to the study data management plan.  
15 DIRECT ACCESS TO SOURCE DATA 
 
During the study, blinded and unblinded monitors will make site visits to review protocol 
compliance, compare eCRF entries and individual subject medical records, assess product 
accountability, and ensure that the study is being conducted according to pertinent regulatory 
requirements as applicable to their study role specified in the clinical monitoring plan. Entries 
in the eCRF will be verified with source documentation. The review of medical records will 
be performed in a manner to ensure that subject confidentiality is maintained and the study 
blind is protected. 
Checking of the eCRF entries and other study electronic systems 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, and/or the sponsor may 
wish to carry out such source data checks and/or on-site audit inspections. Direct access to 


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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 the 
sponsor or designee of the necessary support at all times. 
16 DATA QUALITY ASSURANCE 
The sponsor or designee will conduct a site visit to verify the qualifications of each 
investigator, inspect the site facilities, and inform the investigator of the responsibilities and 
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 
subjects’ source documentation (e.g., medical records). 
17 ARCHIVING OF SOURCE DATA AND OTHER RECORDS 
According to ICH guidelines, essential documents should be retained for a minimum of 
2 years after the last approval of a marketing application in an ICH region and until there are 
no pending or contemplated marketing applications in an ICH region or at least 2 years have 
elapsed since the formal discontinuation of clinical development of the investigational 
product. However, these documents should be retained for a longer period if required by the 
applicable legal requirements. 
18 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 subjects 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.  
19 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. 


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An investigator shall not publish any data (e.g., poster, abstract, or paper) without having 
consulted with the sponsor in advance and having received written authorization. 
 
 


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20 REFERENCES 
1. 
John A McCulloch ET. Macnab's Backache. 4th ed: Williams & Wilkins; 2006. 
2. 
Saal JA, Saal JS. Nonoperative treatment of herniated lumbar intervertebral disc with radiculopathy. 
An outcome study. Spine. 1989 Apr;14(4):431-7. 
3. 
Weber H. Lumbar disc herniation. A controlled, prospective study with ten years of observation. 
Spine. 1983 Mar;8(2):131-40. 
4. 
Peul WC, van Houwelingen HC, van den Hout WB, Brand R, Eekhof JA, Tans JT, et al. Surgery 
versus prolonged conservative treatment for sciatica. The New England journal of medicine. 2007 May 
31;356(22):2245-56. 
5. 
Weinstein JN, Tosteson TD, Lurie JD, Tosteson AN, Hanscom B, Skinner JS, et al. Surgical vs 
nonoperative treatment for lumbar disk herniation: the Spine Patient Outcomes Research Trial (SPORT): a 
randomized trial. Jama. 2006 Nov 22;296(20):2441-50. 
6. 
Smith L. Enzyme Dissolution of the Nucleus Pulposus in Humans. Jama. 1964 Jan 11;187:137-40. 
7. 
Gibson JN, Grant IC, Waddell G. The Cochrane review of surgery for lumbar disc prolapse and 
degenerative lumbar spondylosis. Spine. 1999 Sep 1;24(17):1820-32. 
8. 
Agre K, Wilson RR, Brim M, McDermott DJ. Chymodiactin postmarketing surveillance. 
Demographic and adverse experience data in 29,075 patients. Spine. 1984 Jul-Aug;9(5):479-85. 
9. 
Yamagata T, Saito H, Habuchi O, Suzuki S. Purification and properties of bacterial chondroitinases 
and chondrosulfatases. The Journal of biological chemistry. 1968 Apr 10;243(7):1523-35. 
10. 
Hamai A, Hashimoto N, Mochizuki H, Kato F, Makiguchi Y, Horie K, et al. Two distinct 
chondroitin sulfate ABC lyases. An endoeliminase yielding tetrasaccharides and an exoeliminase 
preferentially acting on oligosaccharides. The Journal of biological chemistry. 1997 Apr 4;272(14):9123-
30. 
11. 
Shrimpton PC, Wall BF, Hart D. Diagnostic medical exposures in the U.K. Applied radiation and 
isotopes : including data, instrumentation and methods for use in agriculture, industry and medicine. 1999 
Jan;50(1):261-9. 
12. 
McGirt MJ, Eustacchio S, Varga P, Vilendecic M, Trummer M, Gorensek M, et al. A prospective 
cohort study of close interval computed tomography and magnetic resonance imaging after primary lumbar 
discectomy: factors associated with recurrent disc herniation and disc height loss. Spine. 2009 Sep 
1;34(19):2044-51. 
13. 
Sampson HA, Munoz-Furlong A, Campbell RL, Adkinson NF, Jr., Bock SA, Branum A, et al. 
Second symposium on the definition and management of anaphylaxis: summary report--Second National 
Institute of Allergy and Infectious Disease/Food Allergy and Anaphylaxis Network symposium. The 
Journal of allergy and clinical immunology. 2006 Feb;117(2):391-7. 


Protocol Number 6603/1133  
Sponsor: Seikagaku Corporation 
Clinical Study Protocol: 
 
 
 
 
 
 
 
 
 
Confidential 
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Version 7.0 
 
 
14. 
Dmitrienko A, Tamhane A. C, Wiens B. L General multistage gatekeeping procedures: Biometrical 
Journal. 2008 Oct 50(5):667-77. 
 
 

SAP_001.pdf: 
Version: 2.0
STATISTICAL ANALYSIS PLAN
12 May 2023
A Multicenter, Randomized, Double-blind, Sham-controlled, 
Comparative Study of SI-6603 in Subjects with Lumbar Disc 
Herniation (Phase 3)
PROTOCOL NUMBER
6603/1133
SPONSORED BY
SEIKAGAKU CORPORATION
6-1, Marunouchi 1-chome, Chiyoda-ku, 
Tokyo 100-0005, Japan
PREPARED BY
This document is confidential and proprietary to Seikagaku Corporation. Acceptance of this document 
constitutes agreement by the recipient that no unpublished information contained herein will be reproduced, 
published, or otherwise disclosed without the prior written approval of Seikagaku Corporation, except that 
this document may be disclosed to appropriate Institutional Review Boards under the condition that they 
keep the information confidential.


 
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DOCUMENT VERSION CONTROL 
Version Number 
Date 
Comments/Changes 
1.0 
30Mar2018 
Created 
1.1 
05DEC2022 
Updated for COVID-19 
pandemic 
Added clarifications on visit 
windowing, diary data averages, 
baseline record selection, worst 
back pain data handling 
Added sensitivity analyses 
Updated multiplicity to use serial 
gatekeeping 
Updated definition of recurrence 
of LDH to clarify treatment 
failure criteria. 
2.0 
12May2023 
Changed odds ratios to 
differences in proportions 
Updated handling of missing 
responder-type endpoints 
Added efficacy subgroup analysis 
Edited for consistency on 30% 
and 50% improvement 
Added clarification around 
handling of baseline and follow-
up averages when randomization 
and injection dates differ 
Updated randomization seeds to 
an appropriate number of digits 
Updated definition of recurrence 
of LDH 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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Seikagaku Corporation
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Statistical Analysis Plan
Protocol No. 6603/1133
12MAY2023
Version: 2.0
Page 4 of 39
APPROVALS
Project Statistician Approval
Seikagaku Corporation Approval
Chief Strategist, Biostatistics & Protocol 
Design
Takayuki Seo, 
Biostatistics Lead
Signature and Date
Signature and Date


 
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TABLE OF CONTENTS 
LIST OF ABBREVIATIONS ............................................................................................ 7 
1. 
PURPOSE OF THE ANALYSES .............................................................................. 9 
2. 
PROTOCOL SUMMARY ........................................................................................ 10 
2.1 
Study Objectives ......................................................................................... 10 
2.2 
Overall Study Design and Plan ................................................................... 10 
2.3 
Study Population ......................................................................................... 10 
2.4 
Treatment Regimens................................................................................... 11 
2.5 
Randomization ............................................................................................ 11 
2.6 
Sample Size Determination ......................................................................... 11 
3. 
GENERAL ANALYSIS AND REPORTING CONVENTIONS.................................. 12 
3.1 
Baseline values ........................................................................................... 12 
4. 
ANALYSIS POPULATIONS ................................................................................... 13 
4.1 
Modified Intention-to-Treat .......................................................................... 13 
4.2 
Per-Protocol ................................................................................................ 13 
4.3 
Safety ......................................................................................................... 13 
5. 
STUDY SUBJECTS ............................................................................................... 14 
5.1 
Disposition of Subjects ................................................................................ 14 
5.2 
Protocol Deviations ..................................................................................... 14 
6. 
DEMOGRAPHICS, BASELINE CHARACTERISTICS, CONCOMITANT 
MEDICATIONS, MEDICAL HISTORY .................................................................... 15 
6.1 
Demographics and Other Baseline Characteristics ..................................... 15 
6.2 
Prior and Concomitant Medications/Therapies ............................................ 16 
6.3 
Medical History ........................................................................................... 16 
7. 
EFFICACY EVALUATION ..................................................................................... 17 
7.1 
Overview of Efficacy Analysis Issues .......................................................... 17 
7.1.1 
Handling of Dropouts or Missing Data ................................................ 17 
7.1.2 
Assessment Time Windows ............................................................... 17 
7.2 
Efficacy Variables ....................................................................................... 18 
7.3 
Analysis Methods ........................................................................................ 19 
7.3.1 
Estimand............................................................................................ 19 
7.3.2 
Primary Efficacy Analyses ................................................................. 19 
7.3.2.1 
Data Handling of Worst Leg Pain .......................................... 20 
7.3.2.2 
Sensitivity analyses ............................................................... 21 
7.3.2.3 
Per Protocol Analyses ........................................................... 22 
7.3.2.4 
Comparison of Results in Subpopulations ............................. 22 
7.3.3 
Secondary Efficacy Analyses ............................................................. 22 
7.3.3.1 
Key Secondary ...................................................................... 22 
7.3.3.2 
Sensitivity Analyses for Key Secondary endpoints ................ 23 
7.3.3.3 
Other Secondary ................................................................... 23 
7.3.3.4 
Composite responder ............................................................ 24 
7.3.3.5 
Recurrence of LDH ............................................................... 25 
7.3.3.6 
Cumulative Distribution Plots ................................................ 26 
7.3.4 
Multiple Comparisons ........................................................................ 26 


 
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8. 
SAFETY EVALUATION ......................................................................................... 27 
8.1 
Overview of Safety Analysis Methods ......................................................... 27 
8.2 
Adverse Events ........................................................................................... 27 
8.2.1 
Treatment-Emergent Adverse Events by System Organ Class and 
Preferred Term .................................................................................. 28 
8.2.2 
Treatment-Emergent Adverse Events by System Organ Class, 
Preferred Term, and Relationship/Severity ........................................ 28 
8.2.3 
Serious AEs, AEs leading to death, Special Interest and 
Significant Treatment-Emergent Adverse Events by System Organ 
Class and Preferred Term .................................................................. 28 
8.3 
Vital Signs, Labs, Imaging Findings, and Other Observations Related to 
Safety ......................................................................................................... 29 
8.3.1 
Vital Signs .......................................................................................... 29 
8.3.2 
Laboratory Tests ................................................................................ 29 
8.3.3 
Imaging Findings ............................................................................... 29 
8.3.4 
Post Treatment Lumbar Surgery ........................................................ 29 
9. 
OTHER ANALYSES .............................................................................................. 31 
10. INTERIM ANALYSES ............................................................................................ 32 
11. CHANGES TO THE ANALYSES PLANNED IN THE PROTOCOL ........................ 33 
12. REFERENCES ....................................................................................................... 34 
13. APPENDICES ........................................................................................................ 35 
13.1 
Schedule of Activities .................................................................................. 36 
13.2 
Randomization Seeds ................................................................................. 38 
14. ATTACHMENTS .................................................................................................... 39 
 


 
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LIST OF ABBREVIATIONS 
AE 
Adverse Event 
ANCOVA 
Analysis of Covariance 
ATC 
Anatomical Therapeutic Chemical 
BMI 
Body Mass Index 
CGIC 
Clinical Global Impression of Change  
CI 
Confidence Interval 
COVID-19 
COronaVIrus Disease of 2019 
eCRF 
electronic Case Report Form 
EQ-5D-5L 
EuroQol Group 5-Dimension Quality of Life 
mITT 
modified Intention-to-treat 
LDH 
Lumbar Disc Herniation 
MAR 
Missing at Random 
MCAR 
Missing Completely at Random 
MCMC 
Markov Chain Monte Carlo 
MedDRA 
Medical Dictionary for Regulatory Activities 
MI 
Multiple Imputation 
MMRM 
Mixed Model for Repeated Measures 
MNAR 
Missing Not at Random 
MRI 
Magnetic Resonance Imaging 
ODI 
Oswestry Disability Index 
PGIC 
Patient Global Impression of Change  
PP 
Per-protocol 
PT 
Preferred Term 
QOL 
Quality of Life 
SD 
Standard Deviation 
SLR 
Straight Leg Raise 
SF-36 
36-item Short Form Health Survey 
SOC 
System Organ Class 
TEAE 
Treatment-emergent Adverse Event 
U 
Units 


 
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VAS 
Visual Analogue Scale 
WPAI 
Work Productivity and Activity Impairment Questionnaire 


 
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1. 
PURPOSE OF THE ANALYSES 
The purpose of the analyses described in this document is to compare the safety and 
efficacy of a single intervertebral disc injection of SI-6603 to a sham injection in subjects 
with lumbar disc herniation (LDH). 


 
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2. 
PROTOCOL SUMMARY 
2.1 
Study Objectives 
The primary objective is to evaluate the efficacy of a single-dose intervertebral disc 
injection of SI-6603 at a dose of 1.25 units (U) compared to control in subjects with LDH 
by comparing the change in worst leg pain during the past 24 hours, as assessed by visual 
analogue scale (VAS), from baseline to Week 13 after injection of the investigational 
product. 
The secondary objectives are to evaluate the efficacy of SI-6603 1.25 U for key 
secondary endpoints, and to demonstrate whether SI-6603 1.25 U is safe and well 
tolerated.    
Key secondary endpoints include: 
• Change from baseline to Week 13 in herniation volume 
• Change from baseline to Week 13 in Oswestry Disability Index (ODI) score 
• Change from baseline to Week 52 in average worst leg pain score during the past 
24 hours over the previous 7 days, as assessed by 100 mm VAS. 
Supportive endpoints may be found in section 7.2. 
2.2 
Overall Study Design and Plan 
Up to three weeks following the screening, subjects will be randomized and injected at 
Week 0. Subjects will receive a single injection of SI-6603 or a sham injection and will 
be followed for 52 weeks for the efficacy and safety evaluations found in the schedule of 
events. Subjects will return for follow-up visits at Weeks 1, 2, 4, 6, 13, 26, 39 and 52. 
2.3 
Study Population 
Subjects will meet the following key criteria: 
• Ages 30 to 70 (inclusive) 
• Have contained posterolateral LDH at either L4-L5 or L5-S1 (or L5-L6): 
o with the presence of demonstrable nerve root impingement, as assessed by 
Magnetic Resonance Imaging (MRI); 
o chief complaint of unilateral radiculopathy and/or radicular leg pain 
corresponding to the ipsilateral leg and distribution of the affected nerve 
root; and 
o positive result of Straight Leg Raise (SLR) test (≤70°) only on the 
ipsilateral leg having chief complaint of radiculopathy corresponding to 
the pain and distribution of the affected nerve root. 
• Symptoms of radiculopathy and/or radicular leg pain only in the unilateral leg 
corresponding to the distribution of the affected nerve root for 6 weeks or more 
but 1 year or less, and which is still ongoing at the time of informed consent. 


 
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• Subjects whose worst leg pain (100 mm VAS) for the 7 consecutive days up to 
the day before randomization meets following conditions: 
o at least 5 worst leg pain scores on the days when not using any rescue 
medications or increasing or adding non-prohibited concomitant 
medications to treat LDH; 
o the mean of the worst leg pain scores is 50 to 90 mm; and 
o the range of fluctuation in worst leg pain scores over the 7 days 
(difference between minimum and maximum scores) is ≤ 25 mm. 
• ≥30% on the ODI at the time of randomization 
The full inclusion and exclusion criteria may be found in the protocol. 
2.4 
Treatment Regimens 
Subjects will be randomized to receive a single dose injection of SI-6603 1.25 U into an 
intervertebral disc or a sham injection. 
2.5 
Randomization 
All eligible subjects will be randomized on a 1:1 basis to SI-6603 or control based on a 
computer-generated randomization schedule. The randomization will be balanced by 
randomly permuted blocks and stratified by site. 
2.6 
Sample Size Determination 
It is planned to enroll approximately 320 subjects, 160 in the SI-6603 group and 160 in 
the control group. 
Sample size estimation is based on using the mean difference in the worst leg pain score 
change from baseline in the primary efficacy analysis. The following assumptions were 
made to compute the sample size: 
• The 2-sample t-test comparing the group means of the change from baseline was 
used. (The 2-sample t-test approximates the test of the null hypothesis based on 
the repeated measures model that will be used in the primary efficacy analysis.) 
• Treatment difference between SI-6603 and control groups of 12 mm 
• Common standard deviation (SD) of 30 mm 
• Dropout rate of 15% 
• Power of 90% 
• Two-sided significance level of 5% 


 
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3. 
GENERAL ANALYSIS AND REPORTING CONVENTIONS 
All efficacy analyses will use a two-sided alpha = 0.05 test unless otherwise stated. P-
values will be rounded to four decimal places. If a p-value is less than 0.0001, it will be 
reported as “<0.0001.” 
Continuous data will be described using descriptive statistics:  sample size, mean, SD, 
median, Q1 and Q3, minimum, and maximum. Minimums and maximums will be 
reported with the same precision as the raw values; medians, Q1, Q3 and means will 
show precision to one decimal place greater than the raw values; SDs will show precision 
to two decimal places greater than the raw values. For example, if height is recorded in 
whole centimeters, min and max will be displayed as whole centimeters, means will be 
shown as xxx.x and SD will be shown as xxx.xx. Data will be displayed in all listings 
sorted by treatment group and subject identification number. Subjects will be identified in 
the listings by the subject identification number concatenated with the investigator 
number. 
When count data are presented, the percentage will be suppressed when the count is zero 
in order to draw attention to the non-zero counts. The denominator for all percentages 
will be the number of subjects with non-missing data in that treatment group within the 
population of interest. 
For the duration of leg pain covariate, if partial dates are provided, then missing dates 
will be imputed as the 15th for a missing day and July for a missing month, consistent 
with prior protocols. 
3.1 
Baseline values 
For visit-based measures, baseline will be the last non-missing value prior to injection. 
For diary-based measures, the baseline will be the average of the scores for the 7 
consecutive days up to the day prior to randomization (independently for worst leg pain 
and worst back pain).  Per the inclusion criteria, subjects should have a minimum of 5 
non-missing values; however, if a subject is inadvertently randomized with fewer values, 
then the baseline will be the mean of the available values from that 7 day period.  Note 
that post-baseline visits were scheduled per the protocol with the injection date as day 1; 
in rare instances, this may be after the randomization date. In these cases, the baseline 
will be anchored around the randomization visit.  Additionally, in the instance that a 
subject is inadvertently entered into the randomization system and assigned a kit on a day 
other than their visit 2A, the anchor date will be the day that they were confirmed to have 
qualified for the trial (typically the day of visit 2A).  


 
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4. 
ANALYSIS POPULATIONS 
Three analysis populations as described below will be utilized in reporting the study 
results. All efficacy analyses will be performed on the modified intention-to-treat (mITT) 
population, with some analyses repeated on the per-protocol (PP) population.  
All safety analyses will be performed on the safety population.  
4.1 
Modified Intention-to-Treat 
The mITT population is defined as all randomized subjects who received the study 
injection, analyzed according to the assigned treatment. 
4.2 
Per-Protocol 
The PP population is defined as all mITT subjects who had no major protocol deviations 
that could affect the primary efficacy assessment. The details of major protocol 
deviations are described in section 5.2, and included subjects will be determined prior to 
unblinding. 
4.3 
Safety 
The safety population is defined as all randomized subjects who received the study 
injection, analyzed according to the treatments subjects received. 
 


 
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5. 
STUDY SUBJECTS 
5.1 
Disposition of Subjects 
A disposition table of subjects will include the number and percentage of subjects for the 
following categories: subjects screened, subjects randomized, subjects treated (safety 
sample), subjects in the mITT sample, subjects in the PP sample, subjects completing 
through Week 13, subjects completed study, and subjects discontinued from the study. A 
separate summary of discontinuations through Week 13 will also be presented. All 
percentages will be based on the number of subjects randomized (with the exception of 
subjects screened). Additionally, the number of subjects excluded from each population 
and reason for exclusion will be presented overall and by site. 
The reasons for study discontinuation will also be summarized in this table. The reason 
for discontinuation may include any of the following: lack of efficacy, death, adverse 
event, lost to follow-up, failure to meet randomization criteria, protocol violation, 
physician decision, withdrawal by subject, pregnancy, study terminated by sponsor, and 
other.  Subjects that do not complete the study will be flagged if they had early 
termination due to confirmed COVID-19, early termination at site discretion due to 
COVID-19, or early termination at subject discretion due to COVID-19; this will 
summarized with the number and percentage of subjects in each category. Only the 
primary reason for study discontinuation will be recorded for a given subject. 
The number and percentage of subjects attending each visit will be summarized.  Due to 
the COVID-19 pandemic, visits could be in-person, remote or a combination; the reason 
for a remote visit could be due to the subject having confirmed COVID-19, at site 
discretion due to COVID-19, at subject discretion due to COVID-19 or other reasons.  
Likewise visits may have been missed or canceled due to the subject having confirmed 
COVID-19, at site discretion due to COVID-19, at subject discretion due to COVID-19 
or other reasons.  Additionally, individual assessments may have been omitted due to 
COVID-19; this is recorded on the CRF.   
The type of visit (in-person, remote, or combination), the reason for remote visits, the 
reason visits were missed and assessments missed due to COVID-19 will be summarized 
with counts and percentages for each visit and treatment group.   
A listing will present data concerning subject disposition and other reasons for 
discontinuation. Additionally, a listing will show the visit attendance, type of visit, reason 
for remote/missed visit, and assessments missed due to COVID-19 for each subject. 
5.2 
Protocol Deviations 
Protocol deviations will be categorized as major or minor prior to database lock and 
unblinding according to Protocol Deviation Plan. Additionally, deviations are categorized 
whether they are related to the COVID-19 pandemic. All recorded protocol deviations 
and their categorization will be presented in a listing.  


 
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6. 
DEMOGRAPHICS, BASELINE CHARACTERISTICS, 
CONCOMITANT MEDICATIONS, MEDICAL HISTORY 
6.1 
Demographics and Other Baseline Characteristics 
Demographics and baseline characteristics will be summarized by treatment for the 
mITT, safety, and PP populations. With the exception of the worst leg pain scores, Week 
0 will be presented unless an outcome is not collected, in which case the screening visit 
will be used. For VAS pain scores, the baseline will be the average of the 7 daily worst 
pain leading up to the randomization visit. Outcomes presented will include: 
• age 
• sex 
• race 
• ethnicity 
• height 
• baseline weight 
• body mass index (BMI) 
• smoking history 
• occupation 
• days since diagnosis 
• herniation site 
• location of herniation 
• location of radicular leg pain 
• days since onset of current radicular leg pain 
• ongoing low back pain caused by herniation 
• VAS pain score for worst leg pain 
• VAS pain score for worst back pain 
• ODI score 
All outcomes except the VAS pain scores and ODI scores will appear in a listing of 
baseline characteristics; VAS pain scores and ODI scores will appear with all other visits 
in the efficacy listings. 
Note that 36-item Short Form Health Survey (SF-36), EQ-5D-5L, and Work Productivity 
and Activity Impairment Questionnaire (WPAI) assessments are collected at baseline; 
however, baseline values of these will be presented only on their associated displays. 


 
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6.2 
Prior and Concomitant Medications/Therapies 
Concomitant medications/therapies include all medications taken at any point following 
the injection of the study therapy; in case of partial dates, a medication will be considered 
to be concomitant unless the partial dates clearly exclude the post-injection period. 
Concomitant medications will be coded using the WHODrug Global using the current 
version at the time coding is first initiated and will be presented with counts and 
percentages by treatment for Anatomical Therapeutic Chemical (ATC) class and 
standardized drug name. Subjects will be counted at most once for a drug and class; this 
will be presented for the safety population. Concomitant medications will also be 
presented in a listing. 
Prior medications include any medications recorded on the electronic case report form 
(eCRF) that were taken at any time prior to injection of study therapy. Prior medications 
will include medications that are ongoing at time of injection of study therapy. Prior 
medications will be presented in a manner parallel to the concomitant medications. 
Additionally, prohibited and restricted medications will be summarized as above and 
presented in a listing. Restricted medications include medications for LDH taken at stable 
dose and regimen as described in protocol section 6.6.2. A separate summary for 
concomitant medication excluding those taken for LDH will also be provided.  
Prior and concomitant therapies will be presented in a listing; prohibited therapies and 
block procedures will be flagged in this listing. 
6.3 
Medical History 
All medical history for the safety population will be presented in a listing. 
The number and percentage of subjects having received nerve block, epidural injection, 
and Facet block will be summarized for each treatment group. 


 
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7. 
EFFICACY EVALUATION 
7.1 
Overview of Efficacy Analysis Issues 
7.1.1 
Handling of Dropouts or Missing Data 
For the efficacy analysis based on repeated-measures models of continuous endpoints, 
missing data will be implicitly handled via a mixed-effect model, without explicit 
imputation. Inferences based on this approach are unbiased under the assumption of 
missing at random (MAR), which is a weaker and more generally true assumption than 
missing completely at random (MCAR).  
For the primary efficacy analysis, sensitivity analysis based on multiple imputation (MI) 
methods that changes imputation methods by missing pattern such as discontinuations 
due to AEs, lack of efficacy, and other will be performed for the mITT population. 
For the analysis of percentages of positive responders by composite definition, no 
imputation will be performed. However, subjects will only be considered responders if 
they meet all criteria, thus, subjects with missing data and dropouts will implicitly be 
treated as non-responders. 
No replacement of any missing data will be made for the safety analyses. 
Additionally, see Section 7.3.2.1 for data handling regarding the VAS pain scores for the 
definition of a non-missing week and data censoring rules.  
7.1.2 
Assessment Time Windows 
All data collected during follow-up will be displayed and analyzed according to the 
actual visit that the data are assigned in the eCRF.  
Study discontinuation visits will be assigned to the corresponding visit if it falls within 
the protocol window for that visit.  For example, a discontinuation visit on day 100 would 
be assigned to Week 13 since it falls within the -7/+14 day window for Week 13. 
However, if scheduled visit data are present, then the discontinuation visit data will not 
be used for that visit. This will be done on a parameter level and discontinuation visit 
values will not be assigned to visits where the assessment was not scheduled to be taken 
(For example, Week 4 does not have MRI, but the discontinuation visit does; even if the 
discontinuation visit falls in the Week 4 window, we would not assign the MRI findings 
to a Week 4 visit). 
Unscheduled assessments (laboratory data, imaging findings or vital signs associated 
with non-protocol clinical visits or obtained in investigating or managing AEs) will be 
included in listings but not summaries of the data.  Likewise, discontinuation visit data 
that do not fall within a protocol-defined window or fall within a window where 


 
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scheduled visit data are already present will not be summarized, but will appear in 
listings.  
7.2 
Efficacy Variables 
The primary efficacy outcome is the change from baseline in the weekly averages of the 
VAS worst leg pain assessed at Weeks 1, 2, 4, 6, 13, 26, 39, and 52. Baseline is defined 
as the average of the 7 daily worst pain measures leading up to the randomization visit. 
Key secondary outcomes include: 
• Change from baseline to Week 13 in herniation volume 
• Change from baseline to Week 13 in ODI score 
• Change from baseline to Week 52 in average worst leg pain score during the past 
24 hours over the previous 7 days, as assessed by 100 mm VAS. 
Supportive outcomes include: 
• Change from baseline in worst leg pain score at each time point 
• Change from baseline in worst back pain score at each time point 
• Change from baseline in ODI score at each time point 
• Percentage of subjects with negative SLR test at each time point 
• Percentage of subjects without hypoesthesia, muscle weakness or hyporeflexia at 
each time point 
• Patient Global Impression of Change (PGIC) score at each time point 
• Clinical Global Impression of Change (CGIC) score at each time point 
• Change from baseline in SF-36 scores at each time point 
• EQ-5D-5L (EuroQol Group 5-Dimension Quality of Life instrument, 5-level 
version) quality of life (QOL) score and VAS score at Week 13 and Week 52 
• WPAI score at Week 13 and Week 52 
• Incidence and amount of rescue medication use over 13 weeks 
• Change from baseline in amount of rescue medication use at each time point 
• Cumulative distribution of percentage change from baseline in worst leg pain 
score at Week 13 and Week 52 
• Cumulative distribution of percentage change from baseline in ODI score at Week 
13 and Week 52 
• Responder rate by composite definition at Week 13 
• Change from baseline in intervertebral disc volume at Week 13 and Week 52 
• Change from baseline in herniation volume at Week 13 and Week 52 
• Incidence of post-treatment surgery for LDH at the same level of investigational 
product injection 
• Number of subjects with recurrence of LDH at Week 52 


 
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7.3 
Analysis Methods 
7.3.1 
Estimand 
Population 
The analysis population will be mITT subjects (randomized and injected) with LDH as defined by 
the protocol inclusion/exclusion criteria. 
Variable 
The primary endpoint will be the change from baseline to Week 13 in the weekly average of daily 
VAS worst leg pain scores. Three days of non-missing values are required for each weekly 
average. 
Intercurrent Events 
Observations following concomitant therapies of lumbar operation, lumbar percutaneous 
nucleotomy, or lumbar intradiscal therapies will be censored.  Otherwise, no special handling will 
be employed for intercurrent events; once injected it is impossible for the subject to go off 
treatment and data will be analyzed as observed. 
Population-Level Summary 
The population-level summary will be the difference in least-square means between treatment 
arms (analyzed as randomized) at Week 13 from the primary analysis model. See Section 7.3.2 
below for details. 
7.3.2 
Primary Efficacy Analyses 
The change from baseline in the worst leg pain scores will be analyzed by a mixed model 
for repeated measures (MMRM) analysis for Week 1 through Week 52 in the mITT 
population. Records analyzed will be the weekly averages at Weeks 1, 2, 4, 6, 13, 26, 39, 
and 52 (see Section 7.3.2.1 for additional details).  
The primary comparison will be the mean change from baseline of the SI-6603 group at 
Week 13 compared with the control group, estimated using this model. The model will 
include the baseline worst leg pain score, treatment, time, treatment-by-time interaction, 
and duration of leg pain as fixed effects.  
An unstructured covariance will be used to model the covariance structure among 
repeated measures. Should the model fail to converge with the type = UN option, a 
compound symmetry structure will be used. Kenward-Roger method will be used for 
computing the denominator degrees of freedom. The missing data will be implicitly 
handled via a mixed-effect model, without explicit imputation. 
The primary efficacy objective will be tested using the null hypothesis that there is no 
difference in the mean change from the pretreatment measure of pain relief (weekly 
average VAS worst leg pain) between SI-6603 and control at 13 weeks. This null 
hypothesis can be expressed as the hypothesis test 


 
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H0: δ13 = 0 vs. HA: δ13 ≠ 0 
where δ13 is the mean difference in the change from the pretreatment measure of pain 
relief (weekly average VAS worst leg pain) between SI-6603 and control at Week 13 
from the model-based estimates of each treatment’s change from pretreatment at those 
visits.  
Worst leg pain score and change from baseline in worst leg pain score will be 
summarized by treatment group and time point. Mean change from baseline over time 
will be summarized in a line graph with error bars.  
7.3.2.1 Data Handling of Worst Leg Pain 
The mean worst leg pain score from 7 consecutive days prior to each visit will be targeted 
as the worst leg pain score for each time point; (the day of the visit itself will not be 
included but will serve as the anchor).  If less than 3 days of worst leg pain scores are 
available in the day interval prior to a visit, alternative 7-day intervals within the 
protocol-specified visit window will be examined.  Finally, for the Week 52 visit only, if 
the actual visit day falls outside of the protocol-defined window, intervals in that window 
will targeted first.  Note that post-baseline visits were scheduled per the protocol with the 
injection date as day 1; in rare instances, this may be after the randomization date.  For 
the purposes of the below algorithm, the injection date is considered to be day 1. 
To calculate the 7-day average, first the worst leg pain score on any of the following days 
will be eliminated: 
• Days after prohibited concomitant therapies of lumbar operation, lumbar 
percutaneous nucleotomy, or lumbar intradiscal therapies occurred, and 
• Days before the previous visit (for example, the Week 2 visit may fall just 5 days 
after Week 1; thus, the days prior to the Week 1 visit will not be considered as 
eligible for inclusion in the 7-day Week 2 average). 
Anchored by the visit date, the average of the consecutive days prior to each visit will be 
calculated. If less than 3 days of worst leg pain scores are available of the 7 consecutive 
days prior to a visit, the following approach will be utilized: 
1. Using the visit target day, each day that would fall within the protocol-defined 
visit window will be identified as the anchor. 
2. For each of those days, the corresponding 7 day interval anchored to that end date 
will be examined and all intervals with a valid average with at least 3 days of data 
will be identified 
3. The interval with the anchor day that falls closest to the visit target day will be 
selected for the average.  In the case of two equidistant valid intervals, the one 
with the later anchor day will be used. 


 
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If an in-person visit is missing altogether, the above process will be used with the 
corresponding visit target day.  If no valid interval can be identified, worst leg pain score 
will be handled as missing at the time point. 
Finally, for the Week 52 visit, if the actual visit day falls outside of the protocol-defined 
window, the following approach will be utilized: 
1. Each day from day 351 to day 379 will be identified as a possible anchor. 
2. For each of those days, the corresponding 7 day interval anchored to that end date 
will be examined and all intervals with a valid average with at least 3 days of data 
will be identified 
3. The interval with the anchor day that falls closest to day 365 will be selected for 
the average.  In the case of two equidistant valid intervals, the one with the later 
anchor day will be used. 
If no valid interval is identified anchoring from day 351 to day 379 (365 +/- 14 days), 
only then will the interval anchored by the out-of-window visit be used. 
The data handling for the worst back pain will use rules identical to those above for worst 
leg pain. 
7.3.2.2 Sensitivity analyses 
As a sensitivity analysis, missing data for participants in the mITT population will be 
imputed via MI. Twenty repeats of the imputation will be performed using Markov Chain 
Monte Carlo (MCMC) assuming non-monotone missing. Where the subject was 
discontinued due to lack of efficacy, due to an AE (with the exception of COVID-19), the 
subject has met the criteria for treatment failure as described in Section 7.3.3.4, or the 
subject’s values are censored due to a prohibited therapy as described in Section 7.3.2.1, 
missing values will be imputed drawing from the baseline values, conditioned on the non-
missing post-baseline values, of all participants in the mITT population under the 
assumption that they are missing not at random (MNAR); duration of leg pain will be 
included as a covariate. 
 If the study medication was discontinued for any other reason, values will be imputed 
within treatment group using MI under the assumption that they are missing at random 
(MAR) with covariates for duration of leg pain, and the weekly average worst leg pain 
score recorded at each time point (including baseline). The MAR approach will also be 
applied for sporadic missing values (prior to discontinuation).  Values missing due to 
COVID-19, whether the result of early termination or sporadic missing values, are 
assumed MAR and unrelated to the endpoint of the weekly average VAS worst leg pain. 
Data will be imputed for the full set of visits as described above and the same output will 
be used as a sensitivity for both the primary at Week 13 and the secondary endpoint at 
Week 52. 


 
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The MMRM analysis as described for the primary will be repeated for each of the 20 sets 
of data and combined using SAS PROC MIANALYZE. See Appendix 13.2 for the list of 
random seeds.  
7.3.2.3 Per Protocol Analyses 
The primary analysis and the key secondary analyses will be repeated on the PP 
population. 
7.3.2.4 Comparison of Results in Subpopulations 
Analyses for the primary endpoint will be conducted for the mITT Population on the 
following subgroups:  
• Age categories:  20-29 years, 30-49 years, 50-59 years and  ≥ 60 years (only 
study 6603/1031 includes 20-29 group, but will be reported and discussed in 
the ISE text) 
• Sex:  Male, Female 
• Race:  White, Black or African American, Asian, and Other. 
• Ethnicity: Hispanic or Latino, Not Hispanic or Latino (applies to Study 
6603/1133 only) 
• BMI categories:  <18.5 kg/m2, 18.5 to  < 25.0 kg/m2, 25.0 to < 35.0 kg/m2, 
and ≥ 35.0 kg/m2 
• Height:  <170 cm, ≥ 170 cm  
• Disc level: L4/L5, L5/S1 (subjects that have the procedure on L6 will be 
grouped with the L5/S1subjects)   
The goal of these subgroup analyses is to explore potential differences in treatment 
response by subgroup.  The analysis and reporting will parallel the primary reporting and 
MMRM model where possible.  If convergence issues arise due to insufficient sample 
size, then descriptive statistics only may be reported for a subgroup. 
7.3.3 
Secondary Efficacy Analyses 
7.3.3.1 Key Secondary 
A longitudinal analysis model will be used as described in the primary efficacy analysis 
for the analyses of change from baseline in the herniation volume at Week 13, change 
from baseline in the worst leg pain score at Week 52, and change from baseline in the 
ODI at Week 13. The baseline value of each outcome will be included as a covariate in 
these models in place of the baseline worst leg pain score (from the primary analysis). 
Note that herniation volume is collected only at Weeks 13 and 52; ODI assessment shares 
the same time points as the primary. 
Key secondary endpoints will be summarized by treatment group and time point. Mean 
change from baseline in key secondary endpoints over time will be summarized in a line 


 
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graph with error bars. Estimated value in key secondary endpoints over time will be 
summarized in a line graph with 95% confidence interval (CI) displayed. 
7.3.3.2 Sensitivity Analyses for Key Secondary endpoints 
An MI approach identical to that used for the sensitivity analysis for the primary endpoint 
will be applied for each key secondary endpoint.  As with the primary, a full set of data 
will be imputed for all visits including Week 52 and the analyses will report results for 
both the Week 13 and Week 52 time points. 
7.3.3.3 Other Secondary 
All endpoints, including the primary and key secondary endpoints, will be summarized 
by treatment group and by time point. The differences of other secondary endpoints 
between the SI-6603 and control groups will be analyzed at each time point they are 
collected as below. 
• A similar longitudinal analysis model will be used as described in the primary 
efficacy analysis for the analysis of change from baseline in pain intensity scores, 
function scores, QOL scores, and volumes (intervertebral disc and herniation), by 
including the corresponding baseline value as the fixed effect instead of the 
baseline worst leg pain score. 
• Percentage change from baseline in intervertebral disc and herniation volumes 
will be summarized in a line graph with error bars. 
• Neurologic status as determined by neurological examinations will be compared 
between treatments with a difference in proportions Z test.  In the case of low 
counts (<5 expected in a cell), a Fisher’s exact test will be used. 
Outcomes will include SLR test, sensation, muscle strength, and deep tendon 
reflex. Counts and percentages in each category will be presented along with 95% 
confidence intervals, the difference in the percentages and its 95% Wald CI.  
Percentages will be reported out of non-missing values. 
• For the global assessments of PGIC score and CGIC score, responder analysis 
with the two best categories as “responder” will be compared between treatments 
with a difference in proportions Z test.  In the case of low counts (<5 expected in 
a cell), a Fisher’s exact test will be used. Counts and percentages in each category 
for the PGIC and CGIC will be presented as well as the responder/non-responder 
counts and percentages along with 95% confidence intervals, the difference in the 
percentages of responders and its 95% Wald CI. Subjects with missing values will 
be considered non-responders. 
• Scores on the WPAI will be analyzed with the analysis of covariance model 
including the baseline value and duration of leg pain as covariates. 
• The incidence of rescue medication use will be compared between treatments 
with a difference in proportions Z test.  In the case of low counts (<5 expected in 
a cell), a Fisher’s exact test will be used. The amount of rescue medication use 
will be analyzed with the Wilcoxon rank sum test. 


 
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• Cumulative distribution of percentage change from baseline in worst leg pain and 
ODI will be generated, and differences between the SI-6603 and control groups in 
the percentages of subjects experiencing a ≥30% and ≥50% improvement in worst 
leg pain score will be compared between treatments with a difference in 
proportions Z test.  In the case of low counts (<5 expected in a cell), a Fisher’s 
exact test will be used. Additionally, the difference in the percentages of 
responders and its 95% Wald CI will be reported. Subjects with missing values 
will be considered non-responders/not having improvement. 
• For the analysis of the percentages of responders by composite definition, 
differences between the SI-6603 and control groups in the percentages of positive 
responders will be compared between treatments with a difference in proportions 
Z test.  In the case of low counts (<5 expected in a cell), a Fisher’s exact test will 
be used. Counts and percentages of responders will be presented along with 95% 
confidence intervals, the difference in the percentages and its 95% Wald CI. See 
section 7.3.3.4 for the definition of composite responder. 
• The number of subjects with recurrence of LDH, percentages and differences 
between the SI-6603 and control groups in the percentages will be reported. See 
section 7.3.3.5 for the definition of recurrence of LDH. 
• Time to post-treatment surgery for LDH will be evaluated by survival analysis 
using Kaplan-Meier methodology and the log-rank test. Counts and percentages 
of subjects with post-treatment surgery will be reported as well as medians and 
quartiles of the time to surgery (if they are defined).   Additionally, the number 
and percentage of subjects with post-treatment surgery for LDH will be reported 
and compared between treatment groups with a Fisher’s exact test.  The 
difference in the percentages of responders and its 95% Wald CI will also be 
reported.  
• Time to post-treatment surgery for LDH will be summarized in a Kaplan-Meier 
plot. 
7.3.3.4 Composite responder  
A composite responder is a subject who meets all 4 criteria below (A, B, C, and 
D) as assessed at Week 13: 
a. 
A reduction of ≥30% in worst leg pain score during the past 24 hours 
assessed by VAS from baseline to Week 13; 
b. 
Improvement of ≥30% in ODI score from baseline to Week 13; 
c. 
Maintenance or improvement of neurologic status (motor, sensory, 
reflexes) from baseline to Week 13; and 
d. 
No “Treatment Failure” 


 
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“Treatment Failure” is defined as a subject to whom any of the conditions 
shown below become applicable until Week 13 after investigational 
product injection: 
i. Use of additional medication/therapy to treat treatment-emergent 
adverse events (TEAEs) or complications associated with 
LDH 
- 
New prohibited medications used for more than 7 days; 
- 
Increase of restricted medications used for more than 7 
days; 
- 
Use of new prohibited therapies; or 
- 
Increase in frequency or intensity of restricted therapies. 
ii. 
Poor response to investigational product that leads the 
investigator to judge it necessary to perform a surgical 
intervention for back pain/leg pain or withdraw from the study 
iii. Increase of measurement value on either vertebral body angle 
formed by flexion or vertebral body translation from baseline 
to values: 
- 
Vertebral body angle formed by flexion of ≥5º, or 
- 
Vertebral body translation of ≥3 mm 
iv. 
Occurrence of treatment related AEs that lead the investigator 
to judge it necessary for the subject to have surgical 
intervention or withdraw from the study 
7.3.3.5 Recurrence of LDH 
Recurrence of LDH is defined as below: 
 
A subject who has all of the following conditions: 
a. The subject shows improvement according to all of the following 
clinical symptoms at Week 13: 
- 
Reduction of ≥30% in worst leg pain score from baseline, 
- 
Improvement of ≥30% in ODI score from baseline, and 
- 
Maintenance or improvement of neurologic status (motor, 
sensory, reflexes) from baseline. 
b. At week 52: 
- 
Subject does NOT have reduction of ≥30% in worst leg pain 
score from baseline, 


 
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- 
Subject does NOT have improvement of ≥30% in ODI score 
from baseline, and 
- 
Maintenance of or experiences worsening of neurologic status 
(motor, sensory, reflexes) from baseline. 
Percentages will be reported out of subjects with any Week 52 data.  If a subject 
has missing values, they will be imputed as negative outcomes (for example, 
missing leg pain will be interpreted as not having 30% reduction). 
7.3.3.6 Cumulative Distribution Plots 
Cumulative distribution plots of percentage change from baseline at Week 13 and Week 
52 will be presented for the worst leg pain and the ODI score. Percentages will be out of 
all subjects, thus subjects with missing data will be counted as not having achieved a 
given percentage of improvement.  Percentage of subjects will be on the Y axis and 
percentage of improvement will be on the X axis. Reference lines will mark 30% and 
50% improvement. 
7.3.4 
Multiple Comparisons 
To control family-wise error rate for multiple tests of the primary and key secondary 
endpoints, serial gatekeeping testing algorithm will be used. 
1. The treatment effect on the primary endpoint will be evaluated at α = 0.05.  
2. If the effect on the primary endpoint is significant, the treatment effect on the key 
secondary endpoint of worst leg pain score at Week 52 will be evaluated using α 
= 0.05.  
3. If worst leg pain score at Week 52 is significant α = 0.05, then the herniation 
volume at Week 13 will be tested at α = 0.05.  
4. If the herniation volume at Week 13 is significant α = 0.05, then the ODI at Week 
13 will be tested at α = 0.05.  
If at any point in the sequence an endpoint fails to meet significance at α = 0.05, then the 
algorithm will be halted and the remaining tests declared non-significant regardless of 
their p-values.  Endpoints and time points other than those above may have p-values 
reported, but none of these will be considered to be statistically significant. 
 


 
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8. 
SAFETY EVALUATION 
8.1 
Overview of Safety Analysis Methods 
All safety analyses will be performed on the safety population (any subject that received 
an injection) and will be presented by the treatment subjects actually received. No 
imputation of missing values will be performed. 
8.2 
Adverse Events  
All AEs will be coded using Medical Dictionary for Regulatory Activities (MedDRA) 
using the current version at the time coding is first initiated. TEAEs will be defined as 
any AEs that were recorded during or following the investigational product injection. 
Significant TEAEs will include TEAEs that result in study discontinuation. TEAEs of 
special interest will include TEAEs associated with hypersensitivity, imaging findings, 
leg pain, and back pain.   
An overall display will show the number and percentage of subjects (with exact 95% CI) 
with TEAEs or treatment-related TEAEs that fall into the following categories: any 
TEAE; TEAE leading to death; serious TEAE; significant TEAE; TEAE associated with 
hypersensitivity; TEAE associated with imaging findings; TEAE associated with leg 
pain; TEAE associated with back pain. TEAEs related to study procedure will be 
summarized. In addition the number of subjects with TEAEs or treatment-related TEAEs 
will be summarized by the following: 
Relationship to Study 
Drug 
Severity 
Time of First 
Occurrence (after 
injection) 
Related AEs 
Mild AEs 
≤ 1 day  
Not Related AEs 
Moderate AEs 
2 – 7 days 
 
Severe AEs 
8 days – 13 weeks 
 
 
>13 weeks 
Subjects experiencing AEs in more than one category will be counted in the most severe 
or most related group. 
Detailed listings of all AEs will include severity and relationship to treatment, as well as 
action taken, subject outcome, and whether the AE is diagnosed or suspected COVID-19. 
Separate listings will be provided of subjects who experience serious TEAEs, significant 
TEAEs, and special interest TEAEs.  Additionally, any information recorded for AEs of 
diagnosed or suspected COVID-19 regarding descriptions of signs/symptoms, treatments, 
diagnostic test results, and the resolution will be presented in a listing. 


 
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8.2.1 
Treatment-Emergent Adverse Events by System Organ Class 
and Preferred Term 
The total number of TEAEs and the number and percentage of subjects with events will 
be presented by system organ class (SOC) and preferred term (PT). Subjects are counted 
once in each SOC and PT. Percentages will be based on the total number of treated 
subjects in the treatment group. SOC will be listed in the Internationally Agreed Order 
(found in MedDRA Data Retrieval and Presentation: Points to Consider, Release 3.2) and 
PTs within a SOC will be listed alphabetically.  
This will be repeated for treatment-related AEs. 
8.2.2 
Treatment-Emergent Adverse Events by System Organ Class, 
Preferred Term, and Relationship/Severity 
The total number of TEAEs and the number and percentage of subjects with events will 
be presented by SOC and PT as described above by relationship to study drug (related, 
not related). At each level (SOC, PT, overall), subjects will be counted as related if they 
have any TEAE within that level that was deemed related. 
Likewise, this presentation will be repeated by severity. Subjects will be counted at the 
highest severity that they experience with a given level of summarization (SOC, PT, 
overall). 
Additionally, TEAEs related to the study procedure will be displayed as above as well as 
broken down by severity. 
8.2.3 
Serious AEs, AEs leading to death, Special Interest and 
Significant Treatment-Emergent Adverse Events by System 
Organ Class and Preferred Term 
The total number of TEAEs and the number and percentage of subjects with events will 
be presented by SOC and PT as described above for serious AEs, TEAEs leading to 
death, special interest TEAEs, and significant TEAEs.  
TEAEs of special interest will include TEAEs associated with hypersensitivity, imaging 
findings, leg pain, and back pain; significant TEAEs will include TEAEs that result in 
study discontinuation. Specific PTs related to each of the special interest groupings will 
be described in the define file for the datasets. 
The number of TEAEs of special interest and percentage of subjects with events will be 
summarized by severity and time of occurrence. Time of first occurrence will be based on 
time from injection and will include the following categories: ≤ 1 day; 2 – 7 days; 8 days 
to 13 weeks; > 13 weeks. 
All the above will be repeated for treatment-related AEs only. 


 
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8.3 
Vital Signs, Labs, Imaging Findings, and Other Observations 
Related to Safety 
8.3.1 
Vital Signs 
Vital signs at each visit and changes from baseline will be summarized descriptively 
using the conventions for continuous variables. A listing of vital signs will be presented 
by treatment group, subject, vital sign, and visit.  
8.3.2 
Laboratory Tests 
Clinical laboratory tests are collected at screening, Weeks 1, 6, 13 and at discontinuation. 
Changes from screening will be summarized descriptively using the conventions for 
continuous variables.  
A listing of laboratory results will be presented by treatment group, subject, lab test, and 
visit.  The results of pregnancy tests and urine drug screens will be presented in separate 
listings. 
8.3.3 
Imaging Findings 
Counts and percentages of significant findings from the MRI and X-ray imaging will be 
presented by treatment for screening, Week 13 and Week 52; results from discontinuation 
visit and last visit for all subjects will be presented separately.  
Findings to be presented will include: 
• 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 
• Changes of vertebral body endplates and adjacent bone marrow as visible by 
MRI. The criteria are as follows: Modic Type 1, Type 2, or Type 3 change in 
vertebral body endplates and adjacent bone marrow. 
Disc height, vertebral posterior angle, and vertebral body translation will be summarized 
by visit for the observed values, the change from baseline, and the percent change from 
baseline (disc height only). Percent change from baseline in disc height, observed value 
of vertebral posterior angle and vertebral body translation will also be summarized in a 
line graph over time. 
Summaries will use the adjudicated values, but all reader data will appear in the listings. 
8.3.4 
Post Treatment Lumbar Surgery 
Counts and percentages of subjects with post-treatment lumbar surgery by Week 52 will 
be presented by treatment. Percentages will be out of subjects with successful contact. 


 
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This will be summarized for any surgery, LDH at a non-target level and surgery not for 
LDH. 


 
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9. 
OTHER ANALYSES 
The association between imaging findings and clinical symptoms will be assessed. The 
following dichotomous imaging findings will be evaluated: 
• 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 
• Changes of vertebral body endplates and adjacent bone marrow as visible by 
MRI: Change of Modic Type 1, Type 2 and Type 3 
For each outcome, treatment and level (decrease in disc height ≥30% and decrease in disc 
height <30%, for example) the following will be reported: 
• Subjects with TEAEs associated with leg pain (number and percentage) 
• Subjects with TEAEs associated with back pain (number and percentage) 
• Subjects with worsening of worst leg pain (number and percentage) 
• Subjects with worsening of worst back pain (number and percentage) 
• Continuous summary statistics of worst leg pain 
• Continuous summary statistics of worst back pain 
These will be reported through Week 13 and Week 52. 


 
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10. 
INTERIM ANALYSES  
  No interim analyses are planned. All final analyses will be performed following 
database lock and unblinding. 


 
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11. 
CHANGES TO THE ANALYSES PLANNED IN THE PROTOCOL 
The protocol-specified MI sensitivity analysis to the primary did not include 
consideration for subject data that is set to missing following a prohibited procedure; this 
has been included among the study outcomes that use the baseline distribution for 
imputation. 
The multiple comparison algorithm has been updated to do a more straightforward serial 
gatekeeping approach. 
The recurrence of LDH endpoint in the protocol references one of the treatment failure 
criteria; because this criteria was nested in other requirements that would conflict with 
the recurrence of LDH criteria, the text was updated to focus on only the applicable 
items. Additionally, surgical intervention was removed as a criteria and the symptom 
criteria were clarified.  
 


 
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12. 
REFERENCES 
1. Dmitrienko A, Tamhane A. C, Wiens B. L General multistage gatekeeping procedures: 
Biometrical Journal. 2008 Oct 50(5):667-77. 


 
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13. 
APPENDICES 


 
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13.1 
Schedule of Activities 
 
Screening 
 
Follow up 
Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
DC 
Week 
-3 
0 
1 
2 
4 
6 
13 
26 
39 
52 
≤ 13 
>13  
Day 
-21 
1 
8 
15 
29 
43 
92 
183 
274 
365 
 
 
 
 
Before 
Injectio
n 
 
After 
Injection 
 
Window (days) 
 
-1 
 
 
±1 
±3 
±3 
±7 
-7, +14 ±14 
±14 
±14 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion 
criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics, medical 
history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant 
medications/ rescue 
medication use 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital signs 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse events 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine drug test 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Neurological examination 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Laboratory testsa 
X 
 
 
 
X 
 
 
X 
X 
 
 
 
X 
 
Pregnancy testb 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Imaging (X-ray, MRI)c 
X 
 
 
 
 
 
 
 
X 
 
 
X 
X 
X 
Central eligibility 
assessment for imaging 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Confirmation of wash out 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Daily diary (VAS pain 
assessment and rescue 
medication use) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Subject educationd 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Distribution of rescue 
medicatione 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
ODI 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
SF-36 
 
X 
 
 
 
 
X  
X 
X 
X 
X 
X 
X 
X 
EQ-5D-5L 
 
X 
 
 
 
 
 
 
X 
 
 
X 
X 
X 
WPAI 
 
X 
 
 
 
 
 
 
X 
 
 
X 
X 
X 
Randomizationf 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Injectiong 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
PGIC 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CGIC 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Telephone call before 
visith 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
 
 
Recurrence of LDH 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
Occurrence of lumbar 
surgeryi 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
Collect remaining rescue 
medication 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X=Essential examination; Solid line means assessment will be made throughout the period, and dotted line means the assessment will 
be made during the 14 consecutive days prior to the visit. 
CGIC = Clinical Global Impression of Change; DC = Discontinuation; EQ-5D-5L = EuroQol Group 5-Dimension Quality of Life 
instrument, 5-level version; LDH = Lumbar Disc Herniation; MRI = Magnetic Resonance Imaging; ODI = Oswestry Disability Index; 
PGIC = Patient Global Impression of Change; SF-36 = 36-Item Short-Form Health Survey; VAS = Visual Analogue Scale; WPAI = 
Work Productivity and Activity Impairment Questionnaire. 
a Laboratory tests are provided as listed in Table 2 of the study protocol. 
b Women of childbearing potential only. Blood test will be performed at Visit 1, and urine test will be performed at Visit 2. 
c If repeat imaging is needed, the window for imaging will be extended by a maximum of an additional 7 days. 
d Subjects will be educated on appropriate expectations around their participation in a clinical study and the importance of reliably 
consistently and accurately reporting their pain throughout the study. 
e If a subject has enough remaining acetaminophen, additional medication will not be provided. 
f Subjects may be randomized on the day before (Day -1) or the day of (Day 1) investigational product administration. 
g Treatment should be administered within 3 weeks after informed consent. If repeat imaging is needed, the window for screening will 
be extended by a maximum of an additional 7 days. 


 
Seikagaku Corporation 
CONFIDENTIAL 
Statistical Analysis Plan 
Protocol No. 6603/1133 
 
12MAY2023 
Version: 2.0 
 
Page 37 of 39 
h Site staff should contact a subject by telephone call and/or other method by a minimum of 14 days before scheduled visit. 
i Subjects who discontinued the study will be followed until the Week 52 Visit. 


 
Seikagaku Corporation 
CONFIDENTIAL 
Statistical Analysis Plan 
Protocol No. 6603/1133 
 
12MAY2023 
Version: 2.0 
 
Page 38 of 39 
13.2 
Randomization Seeds 
The following is the list of seeds to be used for any imputations; they will be used in the 
order that they appear in the production dataset. If the list below is insufficient for the 
number of seeds required, the list will repeat with values 1 greater than those given. 
 
514895564 
763527595 
221543962 
855875309 
919252181 
252975352 
524264245 
800238255 
734425865 
366652284 
 
 
 
 
 
 
 
 
 
 
 


 
Seikagaku Corporation 
CONFIDENTIAL 
Statistical Analysis Plan 
Protocol No. 6603/1133 
 
12MAY2023 
Version: 2.0 
 
Page 39 of 39 
14. 
ATTACHMENTS