Clinical trial NCT03372161
Conditions: Lumbosacral Radicular Pain
Keywords: lumbosacral radicular pain sciatica leg pain
Sponsor: Scilex Pharmaceuticals, Inc.
Start date: 2017-12-08; Completion date: 2022-01-06
Enrollment: 401 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a research study of SP-102, an experimental medication designed to relieve pain in patients with a specific type of leg pain. The medication is given once by your healthcare professional, with a possibility of a second injection as early as about 1 month after the first treatment.

The purpose of the study is to measure how well a single injection of the experimental medication, SP-102, relieves pain. The study will also investigate the side effects of SP-102.

Detailed description:

Arms: arm 1: SP-102 arm 2: Placebo
Interventions: intervention 1: SP-102 intervention 2: Placebo
Intervention descriptions: intervention 1: injection intervention 2: injection

Protocol documents:
Prot_000.pdf: 






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SUMMARY OF CHANGES incorporated with AMENDMENT 2 
This is a summary of changes from the Protocol dated 29 Sep 2017.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
  
 
 
 
 
 
 
 
   
 
 
 
 
 
  
 
 
 
  
 
   
 
 
 
 




















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TABLE OF CONTENTS 
SIGNATURE PAGE ...................................................................................................................2 
SUMMARY OF CHANGES incorporated with AMENDMENT 3 ...........................................3 
SUMMARY OF CHANGES incorporated with AMENDMENT 2 ...........................................4 
SUMMARY OF CHANGES incorporated with AMENDMENT 1 ...........................................5 
SYNOPSIS ...................................................................................................................................6 
TABLE OF CONTENTS ...........................................................................................................14 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ............................................19 
1 
INTRODUCTION .................................................................................................................23 
1.1 Background ........................................................................................................................23 
1.1.1 Lumbosacral Radicular Pain ......................................................................................23 
 
 
1.1.3 SP-102 ........................................................................................................................25 
1.2 Preclinical Studies ..............................................................................................................25 
1.3 Clinical Studies ..................................................................................................................26 
 
1.5 Study Rationale ..................................................................................................................27 
1.6 Dose Rationale ...................................................................................................................27 
1.7 Study Endpoint Rationale ..................................................................................................28 
1.8 Risks and Benefits for Subjects .........................................................................................28 
2 
STUDY OBJECTIVES ..........................................................................................................30 
2.1 Primary Objective ..............................................................................................................30 
2.2 Secondary Objectives.........................................................................................................30 
3 
INVESTIGATIONAL PLAN ................................................................................................31 
3.1 Overall Study Design and Plan ..........................................................................................31 
3.2 Study Duration ...................................................................................................................33 
3.3 Selection of Study Population ............................................................................................33 
3.3.1 Inclusion Criteria .......................................................................................................33 
3.3.1.1 
Screening Visit Inclusion Criteria (D-22 to D-8).............................................................. 33 
3.3.1.2 
Randomization Inclusion Criteria (D1) ............................................................................ 34 
3.3.1.3 
Repeat Injection Inclusion Criteria (4 to 20 weeks following index injection) ................ 35 


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3.3.2 Exclusion Criteria ......................................................................................................35 
3.3.3 Stopping Rules ...........................................................................................................37 
3.3.4 Removal of Subjects from Therapy or Assessment ...................................................37 
3.4 Treatments..........................................................................................................................37 
3.4.1 Details of Study Treatments.......................................................................................37 
3.4.2 Dosage Schedule ........................................................................................................38 
3.4.3 Treatment Assignment ...............................................................................................39 
3.4.4 Drug Packaging and Blinding ....................................................................................39 
3.4.5 Drug Inventory and Accountability ...........................................................................40 
3.4.6 Treatment Compliance ...............................................................................................40 
3.4.7 Rescue Medication .....................................................................................................40 
3.4.8 Prior and Concomitant Illnesses and Medications .....................................................40 
3.4.8.1 
Prior and Concomitant Illnesses ....................................................................................... 40 
3.4.8.2 
Prior and Concomitant Medications ................................................................................. 41 
3.4.8.3 
Prohibited Medications and Substances ............................................................................ 41 
3.4.9 Allowed Medications and Treatments .......................................................................42 
3.5 Assessments .......................................................................................................................43 
3.5.1 Schedule of Assessments ...........................................................................................43 
3.5.2 Study Procedures .......................................................................................................48 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
3.5.3 Repeat SP-102 Administration ..................................................................................55 
 
 


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3.5.4 Unscheduled Visit ......................................................................................................57 
3.5.5 Assessments for Early Termination ...........................................................................58 
3.5.6 Efficacy Assessments.................................................................................................58 
3.5.6.1 
Numeric Pain Rating Scale ............................................................................................... 58 
3.5.6.2 
Oswestry Disability Index................................................................................................. 59 
3.5.6.3 
PainDETECT .................................................................................................................... 59 
3.5.6.1 
Brief Pain Inventory - Short Form .................................................................................... 59 
3.5.6.2 
Clinical and Patient Global Impression Scales ................................................................. 59 
3.5.7 Safety Assessments ....................................................................................................60 
3.5.7.1 
Physical Examination: ...................................................................................................... 60 
3.5.7.2 
General Neurological and Targeted Neurological Examinations: .................................... 60 
3.5.7.3 
Vital Signs and Body Weight: .......................................................................................... 60 
3.5.7.4 
Electrocardiogram: ............................................................................................................ 60 
3.5.7.5 
Laboratory Parameters: ..................................................................................................... 61 
3.5.7.6 
Adverse Events: ................................................................................................................ 61 
3.5.7.7 
Rescue Medication Use .................................................................................................... 61 
3.5.8 Other Assessments .....................................................................................................62 
3.5.9 Appropriateness of Measurements .............................................................................62 
4 
ADVERSE EVENT REPORTING........................................................................................63 
4.1 Definitions and Criteria......................................................................................................63 
4.1.1 Adverse Events ..........................................................................................................63 
4.1.2 Serious Adverse Events .............................................................................................63 
4.1.3 Unexpected Adverse Drug Reactions ........................................................................64 
4.1.4 Abnormal Laboratory Values ....................................................................................64 
4.1.5 Assessing Intensity and Relationship.........................................................................64 
4.2 Reporting Procedures and Requirements ...........................................................................65 
4.2.1 Adverse Events ..........................................................................................................65 
4.2.2 Adverse Events of Special Interest ............................................................................66 
4.2.3 Serious Adverse Events .............................................................................................66 
4.3 Procedures for Documenting Pregnancy during the Study ................................................67 


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5 
DATA MANAGEMENT AND STATISTICAL ANALYSIS ..............................................68 
5.1 Data Management Considerations .....................................................................................68 
5.2 Statistical Considerations ...................................................................................................68 
5.2.1 Sample Size Justification ...........................................................................................68 
5.2.2 Study Data ..................................................................................................................68 
5.2.3 Definition of a Completed Subject ............................................................................69 
5.2.4 Analysis Methods.......................................................................................................69 
5.2.5 Analysis Populations ..................................................................................................70 
5.2.6 Protocol Deviations ....................................................................................................70 
5.2.7 Demographic and Baseline Characteristics ...............................................................70 
5.2.8 Efficacy Analyses ......................................................................................................70 
5.2.8.1 
Primary Efficacy Endpoint ............................................................................................... 72 
5.2.8.2 
Principal Analysis ............................................................................................................. 72 
5.2.8.3 
Secondary Efficacy Endpoints .......................................................................................... 72 
5.2.8.4 
Secondary Efficacy Endpoint Analyses ............................................................................ 73 
5.2.8.5 
Multiplicity ....................................................................................................................... 74 
5.2.9 Safety Analyses ..........................................................................................................74 
5.2.9.1 
Adverse Events ................................................................................................................. 74 
5.2.9.2 
Electrocardiographic Data ................................................................................................ 75 
5.2.9.3 
Laboratory Data ................................................................................................................ 75 
5.2.9.4 
Vital Signs......................................................................................................................... 75 
5.2.9.5 
Neurological Examinations ............................................................................................... 75 
5.2.10 Interim Analyses ........................................................................................................75 
6 
STUDY MANAGEMENT ....................................................................................................76 
6.1 Ethics and Consent .............................................................................................................76 
6.1.1 Regulations and Guidelines .......................................................................................76 
6.1.2 Institutional Review Board/Independent Ethics Committees ....................................76 
6.1.3 Informed Consent.......................................................................................................76 
6.2 Discontinuation of the Study by the Sponsor ....................................................................76 
6.3 Study Documentation.........................................................................................................76 
6.4 Study Monitoring and Auditing .........................................................................................76 
6.5 Retention of Records..........................................................................................................77 


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6.6 Use of Study Findings ........................................................................................................77 
6.7 Publications ........................................................................................................................77 
7 
REFERENCES ......................................................................................................................78 
8 
APPENDICES .......................................................................................................................82 
Appendix A 
Targeted Neurological Exam .................................................................................82 
Appendix B 
Morphine Equivalents ............................................................................................83 
Appendix C 
BMI Table ..............................................................................................................84 
Appendix D 
Instructions for Study Drug Injection ....................................................................85 
Appendix E 
Numeric Pain Rating Scale ....................................................................................88 
Appendix F 
Oswestry Disability Index......................................................................................91 
Appendix G 
PainDETECT .........................................................................................................93 
Appendix H 
Brief Pain Inventory-Short Form ...........................................................................95 
Appendix I 
Clinician Global Impression of Severity and Clinician Global Impression of 
Change ...................................................................................................................97 
Appendix J 
Patient Global Impression of Change ....................................................................98 
Appendix K 
Pain Catastrophizing Scale ....................................................................................99 
Appendix L 
Hospital Anxiety and Depression Scale ...............................................................100 
Appendix M Daily Acetaminophen Log ...................................................................................101 
Appendix N 
Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in 
Preventive Vaccine Clinical Trials. .....................................................................102 
Appendix O 
Itemized Changes made to the Protocol with Amendment 1 ...............................112 
Appendix P 
Itemized Changes made to the Protocol with Amendment 2. ..............................116 
Appendix Q 
Itemized Changes made to Protocol with Amendment 3.....................................153 
 
TABLES 
Table 3.1: 
Details of Investigational Products ....................................................................... 38 
Table 3.2: 
Schedule of Assessments ...................................................................................... 44 
 
FIGURES 
Figure 3.1: 
Study Schematic.................................................................................................... 33 
Figure 3.2: 
Picture of Investigational Product ......................................................................... 40 


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Definition 
α 
alpha 
µg 
microgram 
µmol 
micromole 
ADR 
adverse drug reaction 
AE 
adverse event 
AESI 
adverse event of special interest 
ALT (SGPT) 
alanine aminotransferase (serum glutamic pyruvic transaminase) 
AST (SGOT) 
aspartate aminotransferase (serum glutamic oxaloacetic transaminase) 
BMI 
body mass index 
BPI-SF 
Brief Pain Inventory-Short Form 
bpm 
beats per minute 
C 
Celsius 
CDISC 
Clinical Data Interchange Standards Consortium  
CD/UT 
cognitive debrief and usability testing 
CFR 
Code of Federal Regulations 
CGI 
Clinical Global Impression 
CGIC 
Clinical Global Impression of Change 
CGIS 
Clinical Global Impression-Severity 
Cmax 
maximum concentration 
CRA 
clinical research associate 
CRO 
contract research organization 
CSF 
cerebrospinal fluid 
CV 
coefficient of variation 
D 
day 
DAL 
Daily Acetaminophen Log 
DB 
double-blind 
DDE 
direct data entry 
ECG 
electrocardiogram 
eCOA 
electronic clinical outcome assessment 
eCRF 
electronic case report form 
EOS 
end of study 
ESI 
epidural steroid injection 
ET 
early termination 


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Abbreviation 
Definition 
F 
Fahrenheit 
FAERS 
FDA Adverse Event Reporting System 
FDA 
Food and Drug Administration 
FSH 
follicle stimulating hormone 
g 
gram 
GCP 
Good Clinical Practice 
HADS 
Hospital Anxiety and Depression Scale 
HbA1c 
Hemoglobin A1c 
HIV 
human immunodeficiency virus 
IB 
Investigator’s Brochure 
ICF 
informed consent form 
ICH 
International Council on Harmonisation 
IEC 
independent ethics committee 
 
 
IND 
Investigational New Drug  
INR 
International Normalization Ratio 
IP 
investigational product 
IRB 
institutional review board 
IUD 
intrauterine device 
IWRS 
interactive web recognition system 
LFT 
liver function tests 
MEDD 
Mean Equivalent Daily Dose 
MedDRA 
Medical Dictionary for Regulatory Activities 
mITT 
Modified intent-to-treat (dataset) 
mg 
milligram  
min 
minutes 
mIU 
milli international unit 
mL 
milliliter 
mm 
millimeter 
mmHg 
millimeters of mercury 
MMRM 
mixed model for repeated measures 
MRI 
magnetic resonance imaging 
mRNA 
messenger ribonucleic acid 
NPRS 
Numeric Pain Rating Scale 


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Abbreviation 
Definition 
NSAID 
nonsteroidal anti-inflammatory drug(s) 
ODI 
Oswestry Disability Index 
OL 
open-label 
PCS 
Pain Catastrophizing Scale 
PGIC 
Patient Global Impression of Change 
po 
given by mouth 
PP 
per-protocol (dataset) 
PT 
prothrombin time 
PTT 
partial prothrombin time 
REML 
restricted maximum likelihood 
RLD 
Reference Listed Drug 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SD 
standard deviation 
SDTM 
Study Data Tabulation Model 
SOP 
standard operating procedure 
TEAE 
treatment emergent adverse event 
TF 
transforaminal(ly) 
Tmax 
time to maximum concentration 
US 
United States 
V 
visit 
W 
week 
WBC 
white blood cells 
 
 
 
 
 


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ADMINISTRATIVE STRUCTURE 
The Study Team Contact list is provided in a separate document. 














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of Pharmacovigilance II (DPV) identified 131 FAERS cases of neurological AEs, including 
41 cases of arachnoiditis and other serious neurological AEs (FDA-2014).  Given the large 
number of ESIs, an estimated 9 million are performed annually in the US, these events are rare 
(Benzon-2015).  Even though serious neurological AEs were reported with both types of 
preparation, the case series for FAERS review contained many more reports for particulate 
steroids (n=116) compared with nonparticulate steroids (n=4), with 11 cases not reporting a 
formulation.  All catastrophic events (those resulting in permanent disability or death) reported to 
FAERS were associated with injection of a suspension, whereas only a few cases involving 
temporary symptoms were reported with glucocorticoid solutions (including dexamethasone) 
(Racoosin-2015).   
As SP-102 has been formulated as 
, safety issues are 
not anticipated.   
 
 


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2 STUDY OBJECTIVES 
2.1 
Primary Objective 
The primary objective of this study is to:  
• Evaluate the analgesic effect on average leg pain (as measured by the NPRS in the 
affected leg) (Appendix E) following a single TF injection of SP-102 compared to an 
 
 of placebo over 4 weeks. 
2.2 Secondary Objectives 
The secondary objectives of the study are to:  
• Evaluate degree of disability over time as measured by the Oswestry Disability Index 
(ODI) (Appendix F).  
• Characterize the change of the subject’s radiculopathy symptoms and overall condition 
using PainDETECT (Appendix G), Brief Pain Inventory – Short Form (BPI-SF) 
(Appendix H), Clinical Global Impression of Change (CGIC) (Appendix I), and Patient 
Global Impression of Change (PGIC) (Appendix J).  
• Evaluate the safety of a single and repeat SP-102 TF injection. 
  
 














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24. Involvement in an ongoing worker's compensation claim, disability claim, or litigation 
related to any pain problem, receiving payments for a settled claim, awaiting pending 
payment for a settled claim, or any secondary gain in the opinion of the investigator. 
3.3.3 Stopping Rules 
A single occurrence of an adverse event of special interest (AESI) precludes the subject 
receiving a repeat injection.  Three occurrences of the AESI of the same type across the study 
will trigger stopping of all further dosing until implementation of a safety review.  
3.3.4 Removal of Subjects from Therapy or Assessment 
A subject will be considered to have completed the study when he or she completes the 
W24 (D169) visit.  If a subject is discontinued at any time after randomization into the study, the 
investigator will make every effort to follow the subject and complete the End of Study 
(EOS)/Early Termination (ET) assessments as shown in Section 3.5.1.  Sufficient subjects will 
be enrolled such that 332 subjects complete the study through W4.   
A termination electronic case report form (eCRF) page should be completed for every subject 
who receives IP, whether the subject completes the study or not.  The reason for any early 
discontinuation should be indicated on this form.  The primary reason for a subject discontinuing 
early should be selected from the following standard categories of ET: 
• Adverse Event: Clinical or laboratory events occurred that, in the medical judgment of the 
investigator for the best interest of the subject, are grounds for discontinuation.  This 
includes serious, nonserious AEs and AESI regardless of relation to the IP. 
• Death: The subject died. 
• Withdrawal of Consent: The subject desired to withdraw from further participation in the 
study in the absence of an investigator-determined medical need to withdraw.  If the 
subject gave a reason for withdrawing, it should be recorded in the eCRF. 
• Protocol Violation: The subject’s findings or conduct failed to meet the protocol entry 
criteria or failed to adhere to the protocol requirements (eg, drug noncompliance, failure 
to return for defined number of visits).  The violation necessitated early discontinued 
from the study. 
• Lost to Follow-Up: The subject stopped coming for visits and study personnel were 
unable to contact the subject. 
• Other: The subject was discontinued for a reason other than those listed above, such as 
theft, loss of IP, or termination of study by sponsor. 
3.4 
Treatments 
3.4.1 Details of Study Treatments 
Information about the IPs is provided in Table 3.1.   












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3.5 
Assessments 
Unless otherwise indicated, all assessments will be performed by the investigator or designated 
study personnel and captured into eCRFs.   
3.5.1 Schedule of Assessments 
The procedures to be performed throughout the study are outlined in the Schedule of 
Assessments (Table 3.2).  A detailed description of each assessment may be found in 
Section 3.5.2.   


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subject assignment should remain the same throughout the trial, and eDiaries should only be 
re-assigned for completed/withdrawn subjects.  The current pain intensity “pain now” will be 
measured at every clinic visit and used for assessment of accuracy of pain reporting and 
monitoring of outlier values.  Morning and afternoon pain measurements will be investigated for 
predictability of response.  
3.5.6.2 Oswestry Disability Index 
The ODI (Appendix F) is a validated questionnaire that was first published in 1980 but it was 
updated in 2000 (Fairbank-1980, Fairbank-2000).  The ODI is currently the gold standard for 
measuring degree of disability and estimating quality of life in a person with low back pain.  The 
ODI is questionnaire completed by the subject which contains 10 topics concerning intensity of 
pain, lifting, ability to care for oneself, ability to walk, ability to sit, sexual function, ability to 
stand, social life, sleep quality, and ability to travel.  Each topic category is followed by 
6 statements describing different potential scenarios in the subject’s life relating to the topic.  
The subject then checks the statement which most closely resembles their situation.  Each 
question is scored on a scale of 0-5 with the first statement being zero and indicating the least 
amount of disability and the last statement is scored 5 indicating most severe disability.  The 
scores for all questions answered are summed, then multiplied by 2 to obtain the index (range 0 
to 100).  Zero is equated with no disability and 100 is the maximum disability possible.  The ODI 
will be obtained at Screening, Baseline, W4, W12, and W24.   
3.5.6.3 PainDETECT 
PainDETECT (Appendix G) is a 7-question validated tool to determine the prevalence of 
neuropathic pain in individuals with lower back pain.  The 7 responses are summed for a 
possible score ranging from 0-35.  In addition to the 7 questions, subjects note the course of pain 
(Persistent pain with slight fluctuations; Persistent pain with pain attacks, Pain attacks without 
pain between them; Pain attacks with pain between them) for a total, overall scale score of 0-38.  
Since its development, 4 additional questions have been added but do not contribute to scoring.  
They ask the patient to rate their pain now and over the last for weeks, and to mark on a body 
chart if their pain is radiating to other parts of the body.  PainDETECT will be collected at 
Screening, Baseline, W4, W12, and W24.   
3.5.6.1 Brief Pain Inventory - Short Form 
The BPI-SF (Appendix H) is a 15-item self-rating scale assessing use of medications, as well as 
sensory, and reactive components of pain.  The BPI-SF includes items that will address 
components of sensory pain, including severity, location, chronicity, and degree of relief due to 
therapy.  The BPI-SF also has items that address reactive pain components, including depression, 
suffering, and perceived availability of relief.  Respectable reliability has been demonstrated over 
short intervals using test-retest correlation; worst pain, r=0.93; usual pain, r=0.78; pain now, 
r=0.59.  The BPI-SF will be collected at Screening, Baseline (D1), W4, W12, and W24. 
3.5.6.2 Clinical and Patient Global Impression Scales 
The CGIS (Appendix I) is rated on an 8-point scale, with responses ranging of responses from 
0 (not assessed) and 1 (normal) through 7 (amongst the most severely ill subjects) (to be 
completed prior to IP administration at the Baseline (D1) Visit).  The CGIC (Appendix I) scores 


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range from 0 (not assessed) and 1 (very much improved) through 7 (very much worse) as 
determined by the trained site rater.  The PGIC scores range from 1 (very much improved) 
through 7 (very much worse) as assessed by the subject.  The CGIC and PGIC are obtained at 
each clinic visit following Baseline (D1).   
3.5.7 Safety Assessments 
3.5.7.1 Physical Examination:  
A complete physical examination, including examination of general appearance, skin, neck, eyes, 
ears, nose, throat, heart, lungs, abdomen, lymph nodes, extremities, and musculoskeletal system, 
will be performed at Screening.  Specific musculoskeletal examination focusing on lumbar spine 
and lower extremities to exclude musculoskeletal sources of the predominant pain, such as SI 
joints and trigger points, will be performed in standardized manner and recorded.  Height (in 
inches without shoes) and weight (in pounds) will be recorded at Screening.  
3.5.7.2 General Neurological and Targeted Neurological Examinations:  
A general neurological examination will include evaluation of mental status (awareness of 
person, place, and time), cranial nerves, motor function and balance, sensory exam (ability to 
feel) and reflexes.  A targeted neurological examination demonstrating findings of, focusing on 
signs and symptoms of lumbosacral radiculopathy, including straight leg raise test, will be 
performed according to the checklist (see Appendix A).  Both general and targeted neurological 
exams are to be performed by the same trained clinician throughout the study, if possible.  
Training for conducting examination will be available on video.  General and targeted 
neurological examinations will be performed at Screening, Baseline (D1), W2, W4, W12, and 
W24, as well as if the repeat injection is administered.  
The blinded Investigator will summarize and document the MRI findings based on the Lumbar 
Disc Nomenclature, the clinical presentation, and the Injection Plan in the eCRF prior to 
Baseline (D1). 
3.5.7.3 Vital Signs and Body Weight:  
Vital signs will include systolic and diastolic BP and heart rate.  During the usual clinic visits, 
the subject is to be seated for approximately 3 mins before vital signs are recorded.  During the 
injection procedure, the vital signs will need to be collected while the subject is in prone position 
on the fluoroscopy table (Appendix D).  Vital signs will be recorded at each clinic visit.   
3.5.7.4 Electrocardiogram:  
Standard 12-lead ECGs will be measured on the site machines at Screening.  The ECG results 
will be documented in the eCRF. 




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3.5.8 Other Assessments 
Pain Catastrophizing Scale: PCS (Appendix K) is used to assess pain as a baseline 
characteristic only at Screening (Sullivan-1995).  It was developed to quantify a subject’s pain 
experience by asking how they feel and what they think about when they are in pain.  Items on 
this scale were developed from clinical and experimental research on catastrophic thinking and 
its relation to experience of pain.  The PCS is a 13-item instrument that can be completed and 
scored in less than 5 mins.  The PCS requires a reading level of approximately Grade 6. 
Hospital Anxiety and Depression Scale: HADS (Appendix L) is commonly used to determine 
a subject’s anxiety and depression levels.  The scale is comprised of 14 items rated on a scale of 
0-3; 7 items focused on anxiety symptoms and 7 items focused on depression symptoms.  The 
HADS will be used for inclusion criteria and completed at Screening only.  A score of 11-14 on 
either the depression or anxiety subscale is indicative of moderate symptomatology. A score of 
≥15 on either the depression or anxiety subscale is indicative of severe symptomatology (Snaith-
1994, Turk-2015). Subjects with HADS scores ≥ 15 will be excluded from this study 
(Zigmond-1983). 
3.5.9 Appropriateness of Measurements 
All assessments to be used in this study are commonly used, standard measurements frequently 
seen in radiculopathy studies. 
 
 


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4 ADVERSE EVENT REPORTING 
Throughout the course of the study, after signing the ICF, all AEs will be monitored and 
recorded on an AE eCRF, including the AE’s description, start and end date, seriousness, 
severity, action taken, and relationship to the IP.  If AEs occur, the first concern will be the 
safety of the study subjects.  All AEs will be followed until resolved or stable and the outcome 
documented on the eCRF. 
4.1 
Definitions and Criteria 
4.1.1 Adverse Events 
An AE is any untoward medical occurrence in a subject or clinical investigation subject 
administered a pharmaceutical product and which does not necessarily have to have a causal 
relationship with this treatment (ICH-E2A-1996).  An AE can therefore be any unfavorable and 
unintended sign (including an abnormal laboratory finding, for example), symptom, or disease 
temporally associated with the use of a medicinal product, whether considered related to the 
medicinal product or not. 
Medical interventions such as surgeries, diagnostic procedures, and therapeutic procedures are 
not AEs but the action taken to treat the medical condition.  They should be recorded as 
treatment of the AEs. 
4.1.2 Serious Adverse Events 
A serious adverse event (SAE) or reaction is any untoward medical occurrence that at any dose: 
• Results in death 
• Is life-threatening 
• Requires inpatient hospitalization or prolongation of existing hospitalization 
• Results in persistent or significant disability or incapacity 
• Is a congenital anomaly or birth defect 
• Is an important medical event (eg, 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; malignancy tumors 
[histologically different from primary tumor]) 
Note: The term “life-threatening” in the definition of “serious” refers to an event in which the 
subject was at risk of death at the time of the event; it does not refer to an event that 
hypothetically might have caused death if it were more severe.   
Medical and scientific judgment should be exercised in deciding whether expedited reporting is 
appropriate in other situations, such as important medical events that may not be immediately 
life-threatening or result in death or hospitalization, but may jeopardize the subject or may 
require intervention to prevent one of the other outcomes listed in the definition above.  These 
should also usually be considered serious. 


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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. 
Seriousness (not severity) serves as a guide for defining regulatory reporting obligations.  An 
SAE is not necessarily severe; eg, an overnight hospitalization for a diagnostic procedure must 
be reported as an SAE even though the occurrence is not medically serious.  By the same token, 
a severe AE is not necessarily serious: nausea of several hours’ duration may be rated as severe 
but may not be considered serious. 
4.1.3 Unexpected Adverse Drug Reactions 
An unexpected adverse drug reaction (ADR) is a reaction for which the nature or severity is not 
consistent with the applicable product information (IB, SP102-IB-2015).  Until product 
information is amended, expedited reporting is required for additional occurrences of the 
reaction.  Reports that add significant information on specificity or severity of a known, already 
documented SAE constitute unexpected events.  For example, an event more specific or more 
severe than described in the IB would be considered “unexpected.”  Specific examples would be 
(a) acute renal failure as a labeled ADR with a subsequent new report of interstitial nephritis and 
(b) hepatitis with a first report of fulminant hepatitis. 
Guidance on reporting AEs and SAEs is described in Section 4.2. 
4.1.4 Abnormal Laboratory Values 
Any abnormality (Appendix N) in a laboratory value that is new in onset or which has worsened 
in severity or frequency from the baseline condition and meets 1 of the following criteria will be 
recorded on the AE pages of the eCRF: 
• Requires therapeutic intervention or diagnostic tests 
• Leads to discontinuation of IP 
• Has accompanying or inducing symptoms or signs 
• Is judged by the investigator as clinically significant 
4.1.5 Assessing Intensity and Relationship 
All AEs will be assessed on 2 descriptive parameters: intensity and relationship to the IP: 
• Intensity refers to the severity of an event and references impact on a subject’s 
functioning. 
• Relationship refers to the likelihood that the event being assessed was caused by the IP. 
Intensity 
Each AE will be classified according to Appendix N. 
When changes in the intensity of an AE occur more frequently than once a day, the maximum 
intensity for the experience should be noted.  If the intensity category changes over a number of 
days, those changes should be recorded separately (with distinct onset dates). 


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Relationship 
Each AE will be assessed as to its relationship to the IP, based on the following criteria.  
Although the attribution by the investigator will be collected for reported events, for analytic 
purposes a temporal association with the use of the IP will be assumed sufficient for at least 
plausible association. 
Investigators are required to assess the causal relationship (ie, whether there is reasonable 
possibility that the study drug caused the event) using the following definitions: 
Unrelated: 
A clinical event, including laboratory test abnormality, with a temporal 
relationship to study drug administration that makes a causal relationship 
improbable, and/or in which other drugs, chemicals or underlying disease 
provide plausible explanations of the event. 
Possibly Related: 
A clinical event, including laboratory test abnormality, with a reasonable 
time sequence to administration of the study drug, but that could also be 
explained by concurrent disease or other drugs or chemicals.  Information 
on study drug causality may be lacking or unclear. 
Probably Related: 
A clinical event, including laboratory test abnormality, with a reasonable 
time sequence to administration of the study drug, unlikely to be attributed 
to concurrent disease or other drugs or chemicals, and that follows a 
clinically reasonable response on re- administration (rechallenge) or 
withdrawal (dechallenge) of the study drug. 
Definitely Related:  
A clinical event, including laboratory test abnormality, with a temporal 
relationship to study drug administration that makes a causal relationship 
definite and is clearly related to use of the IP. 
When assessing the relationship to the IP, the following criteria will be considered: 
• Positive rechallenge 
• Positive dechallenge (resolution upon stopping suspect the IP, in absence of other 
intervention or treatment) 
• Known class effect 
• Biological plausibility 
• Lack of alternative explanation—concomitant drug or disease 
4.2 
Reporting Procedures and Requirements 
4.2.1 Adverse Events 
AEs occurring after the subject signs the ICF until the 30 days after the last study visit will be 
recorded.  Any AEs occurring before the start of treatment (ie, before the first dose of the IP)” 
will be recorded in the medical history.  Also, the sign, symptom, or disease present before 
starting the treatment period are only considered AEs if they worsen after starting the treatment 
period. 
If a subject has new or worsening pain, or onset of new neurological symptoms, a follow-up MRI 
may be obtained after consultation with the Medical Monitor.   




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All recorded SAEs, regardless of relationship to study treatment, will be followed up until 
resolution, stabilization, or the subject is lost to follow-up and cannot be contacted.  In 
circumstances where the Investigator is unable to contact the subject, the Investigator must 
provide a written statement to 
 confirming that the subject is lost to follow-up.  SAEs 
that are ongoing at V5 (D29) should be followed until resolved. 
Additional follow-up information must be reported in the eCRF within 24 hours of awareness 
following Investigator (or site) awareness of the information.  The Investigator should not delay 
reporting an SAE to obtain additional information.  Additional information, when available, 
should be reported to 
 by the reporting procedures described 
above. 
The sponsor or its representative will be responsible for determining and in turn, reporting SAEs 
to regulatory authorities per the applicable regulatory requirements. 
4.3 
Procedures for Documenting Pregnancy during the Study 
Pregnancy occurring in a female subject should be reported to 
 
within 24 hours of becoming aware of the event using the pregnancy eCRF.  The investigator 
will also: (1) notify the subject’s physician that the subject may have been treated with SP-102 
and (2) follow the progress of the pregnancy to term and document the outcome of the 
pregnancy.  Pregnancy outcome information should be forwarded to sponsor/
 when 
available.  
Any pregnancies will be followed through delivery or premature termination.  If a subject 
becomes pregnant during the study, any complications of that pregnancy such as abortion 
(spontaneous or induced), premature birth, or congenital abnormality will be captured as SAEs.  
In the event the eCRF system is unavailable, a back-up paper Pregnancy Reporting Form will be 
available for site staff to complete following reporting guidelines as outlined in Section 4.2.2. 
 
 
















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Any TEAEs will be summarized by treatment group, for each post-randomization treatment 
period: 
• Occurring after the randomization injection, but prior to a second injection (of SP-102) 
• Occurring after the second injection (of SP-102) 
5.2.9.2 Electrocardiographic Data 
A listing of 12-lead ECG parameter results obtained at Screening will be presented.   
5.2.9.3 Laboratory Data 
Mean changes from Baseline (D1) at each post-baseline time point for each laboratory variable 
will be presented.  In addition, each reading will be classified as below, within, or above normal 
range, based on ranges supplied by the laboratory used.  Shift tables for the baseline and 
follow-up measurements will be presented. 
5.2.9.4 Vital Signs 
Summary statistics for the absolute vital sign value and the changes from baseline will be 
presented by treatment group for each visit, for each of the following vital signs: 
• Systolic blood pressure (mmHg) 
• Diastolic blood pressure (mmHg) 
• Heart rate (bpm) 
Vital sign values will be categorized into the following potential clinical concern categories if 
applicable and summarized. 
Vital Sign 
Potential Clinical Concern Categories 
Systolic blood pressure 
≥ 160 mmHg 
Diastolic blood pressure 
≥ 100 mmHg 
Heart rate 
< 60 or > 100 bpm 
5.2.9.5 Neurological Examinations 
General neurological and targeted neurological examination results will be summarized 
descriptively over time and included in listings. 
5.2.10 Interim Analyses 
No interim analysis is planned for this study.  Note that the study will be unblinded and the 
primary analysis will be completed after all subjects complete the 12-week assessments and data 
are cleaned.  Subjects in the OL safety extension portion of the study will continue through W24.  
No efficacy data in the first 12 weeks of the study will change after the primary analysis is 
completed. 
 
 


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6 STUDY MANAGEMENT 
6.1 
Ethics and Consent 
6.1.1 Regulations and Guidelines 
The study will be performed in accordance with this protocol, US investigational new drug 
(IND) regulations (21 CFR 312), ICH guidelines for Good Clinical Practice (GCP), the 
regulations on electronic records and electronic signature (21 CFR 11), and the most recent 
guidelines of the Declaration of Helsinki.  
6.1.2 Institutional Review Board/Independent Ethics Committees  
Conduct of the study must be approved by an appropriately constituted institutional review board 
(IRB).  Approval is required for the study protocol, protocol amendments, ICFs, subject 
information sheets, and advertising materials.  No IP will be shipped to a site until written IRB 
authorization has been received by the sponsor or its representative. 
6.1.3 Informed Consent 
For each trial subject, a written ICF will be obtained before any protocol-related activities.  As 
part of this procedure, the investigator or a designated representative must explain orally and in 
writing the nature, duration, and purpose of the study, and the action of the IP in such a manner 
that the subject and (if applicable) appointed guardian are aware of the potential risks, 
inconveniences, or adverse effects that may occur.  Subjects should be informed that they may 
withdraw from the study at any time.  They will receive all information that is required by 
federal regulations and ICH guidelines.  The principal investigator or a designated representative 
will provide the sponsor or its representative with a copy of the IRB-approved ICF before the 
start of the study. 
6.2 
Discontinuation of the Study by the Sponsor 
The sponsor reserves the right to discontinue the study at this site or at multiple sites for safety or 
administrative reasons at any time.  A site that does not recruit at a reasonable rate may be 
discontinued.  Should the study be terminated, and/or the site closed for whatever reason, all 
documentation and IP pertaining to the study must be returned to the sponsor or its 
representative. 
6.3 
Study Documentation 
By signing a copy of Form FDA 1572, the principal investigator acknowledges that he/she has 
received a copy of the IB on SP-102 and assures the sponsor that he/she will comply with the 
protocol and the provisions stated in Form FDA 1572.  No changes in this protocol can be made 
without the sponsor’s written approval. 
6.4 
Study Monitoring and Auditing 
This study will be monitored for quality assurance at all stages of its development by the clinical 
research personnel employed by the sponsor or its representative.  Monitoring will include 
personal visits and telephone communication to assure that the investigation is conducted per the 
protocol, standard operating procedures, Guidelines of GCP, and applicable regulatory 
requirements.  Quality control procedures will be applied to each stage of data handling to ensure 
that all data are reliable and have been processed correctly.  Remote and on-site review of eCRFs 











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Statistical Analysis Plan
Corticosteroid Lumbar Epidural Analgesia for Radiculopathy (C.L.E.A.R.)
Protocol Number: SP-102-02
Version 2.0
Issue Date: 20-AUG-2021
Previous Version
Version 1.0, Issue Date 04-NOV-2020
Author: 




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Table of Contents
1
LIST OF ABBREVIATIONS .............................................................................5
2
INTRODUCTION...............................................................................................7
3
STUDY OBJECTIVES .......................................................................................8
3.1
Primary Objective........................................................................................................... 8
3.2
Secondary Objectives...................................................................................................... 8
4
ENDPOINTS.......................................................................................................9
4.1
Primary Efficacy Endpoint ............................................................................................. 9
4.2
Secondary Efficacy Endpoints........................................................................................ 9
4.3
Other secondary endpoints.............................................................................................. 9
4.4
Safety Endpoints........................................................................................................... 10
5
SAMPLE SIZE..................................................................................................10
6
RANDOMIZATION .........................................................................................11
7
PLANNED ANALYSES...................................................................................11
7.1
Analysis and Reporting Periods.................................................................................... 11
7.2
Analysis Population ...................................................................................................... 12
7.2.1
Screened Population...................................................................................................... 12
7.2.2
Safety Analysis Population........................................................................................... 12
7.2.3
Modified Intent-to-Treat (mITT) Population................................................................ 12
7.2.4
Per Protocol Population ................................................................................................ 13
7.2.5
Completed Subject........................................................................................................ 13
7.3
Derived Data................................................................................................................. 14
7.3.1
Race............................................................................................................................... 14
7.3.2
Baseline......................................................................................................................... 14
7.3.3
Duration/Study Day/Time............................................................................................. 14
7.3.4
Conventions for Missing and Partial Dates .................................................................. 15
7.3.5
Missing/Partial Start/Stop Date of Adverse Events and Concomitant Medications..... 15
7.3.6
Inexact Values............................................................................................................... 16
7.3.7
Electrocardiogram Data ................................................................................................ 16
7.3.8
Unscheduled Visits ....................................................................................................... 16
7.3.9
Early Termination Assessments.................................................................................... 16
7.3.10 Randomization Strata.................................................................................................... 16
7.4
Conventions .................................................................................................................. 17


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7.4.1
Decimal Places.............................................................................................................. 19
7.5
Subject Disposition....................................................................................................... 19
7.6
Protocol Deviations....................................................................................................... 20
7.7
Baseline Comparability................................................................................................. 20
7.8
Medical History ............................................................................................................ 20
7.9
Prior and Concomitant Medications ............................................................................. 21
7.10
Exposure to Study Drug................................................................................................ 21
7.11
Treatment Compliance.................................................................................................. 22
7.12
Efficacy Analyses ......................................................................................................... 22
7.12.1 Primary Endpoint.......................................................................................................... 22
7.12.2 Primary Efficacy Analysis ............................................................................................ 23
7.12.3 Sensitivity Analysis ...................................................................................................... 24
7.12.4 Key Secondary Endpoints............................................................................................. 26
7.12.5 Key Secondary Analysis............................................................................................... 26
7.12.6 Other Secondary Endpoints and Analysis..................................................................... 27
7.13
Safety Analyses............................................................................................................. 40
7.13.1 Adverse Events ............................................................................................................. 40
7.13.2 Laboratory Data ............................................................................................................ 42
7.13.3 Vital Signs..................................................................................................................... 43
7.13.4 Electrocardiogram Data ................................................................................................ 43
7.13.5 Physical Examination.................................................................................................... 44
7.13.6 Neurological Examination ............................................................................................ 44
8
INTERIM ANALYSIS......................................................................................44
9
DATA SAFETY MONITORING BOARD ANALYSIS .................................44
10 POST-HOC ANALYSIS...................................................................................44
11 CHANGES TO PLANNED PROTOCOL ANALYSIS ...................................44
12 REFERENCES ..................................................................................................47
13 LIST OF TABLES, FIGURES AND LISTINGS .............................................48


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1
LIST OF ABBREVIATIONS
Abbreviation
Definition
AE
adverse event
AICC
corrected Akaike’s information criterion
ALT
alanine aminotransferase (serum glutamic-pyruvic transaminase)
ANCOVA
analysis of covariance
ANOVA
analysis of variance
AST
aspartate aminotransferase (serum glutamic oxaloacetic transaminase)
ATC
Anatomical Therapeutic Chemical
BMI
body mass index
BPI-SF
Brief Pain Inventory-Short Form
bpm
beats per minute
CDISC
Clinical Data Interchange Standards Consortium 
CGIC
Clinical Global Impression of Change
CI
Confidence Interval
C.L.E.A.R.
Corticosteroid Lumbar Epidural Analgesia for Radiculopathy
CS
clinically significant
CSR
clinical study report
DB
double-blind
DSMB
data safety monitoring board
ECG
electrocardiogram
eCRF
Case Report Form
EOS
end of study
ET
early termination
g
gram(s)
HIV
human immunodeficiency virus
IP
independent programming
IPr
investigational product


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Abbreviation
Definition
IWRS
interactive web recognition system
MAR
missing at random
MedDRA
Medical Dictionary for Regulatory Activities
mITT
modified intent-to-treat (data population)
mg
milligram 
mmHg
millimeters of mercury
MMRM
mixed model for repeated measures
NCS
not clinically significant
NPRS
Numeric Pain Rating Scale
ODI
Oswestry Disability Index
OL
open-label
PBO
placebo
PGIC
Patient Global Impression of Change
PP
Per protocol
REML
restricted maximum likelihood
SAE
serious adverse event
SAP
statistical analysis plan
SD
standard deviation
TEAE
treatment emergent adverse event
TF
transforaminal(ly)
WBC
white blood cells




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hours prior to recording an NPRS score.  Doses of rescue medication and time taken will be 
collected in the eDiaries until Week 12 and thereafter as a concomitant medication.  
The subject will complete the eDiary twice daily approximately 12 hours apart (±2 hours) to record 
their NPRS scores for pain in the previous 12 hours for 12 weeks following index injection.  
Thereafter, NPRS scores will be recorded at clinic visits. 
All subjects will be seen at the clinic on Day 15, and every 4 weeks (ie, Week 4 [Day 29], Week 
8 [Day 57], Week 12 [Day 85], Week 16 [Day113], Week 20 [Day 141], and Week 24 [Day 169]) 
after the DB index injection for up to 24 weeks.  Subjects receiving the OL repeat SP-102 injection 
will also be seen at the clinic 14 days after the repeat injection and continue the double-blind 
planned visits as well.  Subjects will also be contacted by telephone by the site staff 2 days after 
each IPr injection to discuss their progress, any medications they are taking, and if they have had 
any adverse events (AEs).
3
STUDY OBJECTIVES
3.1 Primary Objective
The primary objective of this study is to: 
x
Evaluate the analgesic effect on average leg pain (as measured by the NPRS in the 
affected leg) following a single TF injection of SP-102 compared to an
 injection of 
placebo over 4 weeks.
3.2 Secondary Objectives
The secondary objectives of the study are to: 
x
Evaluate degree of disability over time as measured by the Oswestry Disability Index 
(ODI). 
x
Characterize the change of the subject’s radiculopathy symptoms and overall condition 
using PainDETECT, Brief Pain Inventory-Short Form (BPI-SF), Clinical Global 
Impression of Change (CGIC), and Patient Global Impression of Change (PGIC). 
x
Evaluate the safety of a single and repeat SP-102 TF injection.


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4
ENDPOINTS
4.1 Primary Efficacy Endpoint
The primary efficacy endpoint is the mean change from Baseline (D1) to Week 4 in the mean 
NPRS average pain score in the affected leg.
 
4.2 Secondary Efficacy Endpoints
The key secondary efficacy endpoint is:
x
The change in ODI total score from Baseline (D1) to Week 4.
4.3 Other secondary endpoints
Other secondary endpoints are:
x
PGIC at Week 2, Week 4, Week 8, and Week 12. 
x
The time to repeat injection of SP-102 from index injection.
x
Proportion of subjects receiving repeat injection.
x
The mean change from Baseline (D1) to Week 2, Week 4, Week 8, and Week 12 in the 
mean NPRS average pain score in the affected leg. 
x
The mean change from Baseline (D1) to Week 2, Week 4, Week 8, and Week 12 in the 
mean NPRS worst pain in the affected leg.
x
The mean change from Baseline (D1) to Week 2, Week 4, Week 8, and Week 12 in the 
mean NPRS current pain score in the affected leg. 
x
The mean change from Baseline (D1) in the ODI total score to Week 12.
x
The mean change in PainDETECT from Baseline (D1) to Week 4 and Week 12.
x
The mean change in BPI-SF score from Baseline (D1) to Week 4 and Week 12.


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x
Proportion of subjects achieving a response of 30%, 50%, and 75% reductions from 
Baseline (D1) in mean NPRS average pain score in the affected leg at Week 2 and Week 4.
x
The mean change from Baseline (D1) to Week 2, Week 4, Week 8, and Week 12 in the 
mean NPRS average pain score in the lower back. 
x
CGIC at Week 2, Week 4, Week 8, and Week 12.
x
Cumulative use of rescue medication (mg of acetaminophen)
x
Time to first rescue medication dose.
x
Proportion of subjects requiring rescue medications.
x
Percent of rescue medication free days.
x
The mean change from Baseline (D1) to Week 4 in the mean morning (AM) NPRS 
average pain score in the affected leg.
x
The mean change from Baseline (D1) to Week 4 in the mean evening (PM) NPRS 
average pain score in the affected leg.
4.4 Safety Endpoints
x
Adverse Events
x
Change from Baseline (D1) in laboratory parameters
x
Change from Baseline (D1) in vital signs
x
Change from Baseline (D1) in neurological examination
5
SAMPLE SIZE
 
 
 
 
 
 
 
  


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6
RANDOMIZATION
Using an Interactive Web Response System (IWRS), on D1, the site staff or research pharmacist 
will contact the IWRS after the Investigator has confirmed that the subject fulfills all the 
inclusion/exclusion criteria. The IWRS will assign a randomization number to the subject, which 
will be used to link the subject to a treatment arm.  The research pharmacist will prepare the 
appropriate IP and deliver it to study staff in preparation for injection. 
A randomization schedule will be employed to facilitate effective randomization and allocation 
concealment.  The schedule will involve a block randomization technique, randomly assigning 
participants within blocks based on a 1:1 allocation ratio.  The randomization schedule will be 
stratified by study site.
7
PLANNED ANALYSES
No statistical analysis plan (SAP) prepared in advance of the data can be absolutely definitive and 
the final clinical study report (CSR) may contain additional tables or statistical tests if warranted 
by the data obtained.  The justification for any such additional analyses will be fully documented 
in the final CSR.
7.1 Analysis and Reporting Periods
Baseline, efficacy, and safety data will be summarized for the following analysis periods:
x
Primary analysis period which includes data from baseline through 4 weeks of treatment  
x
Secondary analysis period which includes data from baseline to end of study (Week 24)
Also, there are two reporting periods in this study in which for each reporting period, data are 
summarized for both the primary and secondary analysis periods. These reporting periods are as 
follows:
x
Primary analysis:
This is the final inferential analysis of all efficacy endpoints, along with analysis of the 
safety endpoints up to Week12, which will be performed after all subjects complete the 
12-week assessments and all data are cleaned.
 
 
 




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7.2.4
Per Protocol Population
This will include all subjects in the mITT population who do not have a major protocol deviation.  
Major protocol deviations will be reviewed and determined prior to unblinding.  The Per Protocol 
(PP) population will be determined prior to treatment unblinding and will be used for supportive 
sensitivity analyses.
Subjects excluded from the analysis populations and the reason for their exclusion will be listed in 
Appendix 16.2.
7.2.5
Completed Subject
For the purposes of analysis, there are 3 types of completers in this trial:
x
A Primary Efficacy Endpoint Completer is defined as one who receives an index 
injection and who has enough data to calculate data for the primary analysis period (i.e. 
first four weeks) regardless if Week 4 visit was completed.
 
 
 
 
 
 
x
A 12-week Completer is defined as one who receives an index injection and completes 
the study through Week 12.
x
A 24-week Completer is defined as one who receives an index injection and completes 
the study through Week 24.
A subject does not necessarily have to complete all visits up to Week 12, or Week 24 to be 
considered as a 12-week Completer or 24-week Completer respectively.  As long as the Week 12 
or Week 24 visits are completed, the subject will be considered as a 12-week Completer or 24-
week Completer respectively.


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7.3 Derived Data
This section describes the derivations required for statistical analysis. Unless otherwise stated,
variables derived in the source data will not be re-calculated.
 
 
7.3.1
Race
If more than one race category has been selected for a subject, these race categories will be 
combined into a single category labeled “Multiple Race” in the summary tables. The listings will 
reflect the original selected categories. 
7.3.2
Baseline
Except otherwise specified, baseline is defined as the last non-missing value (either scheduled, 
unscheduled or repeat) before the subject receives the first dose of SP-102 TF or placebo 
 
injection on D1. Baseline calculations for variables collected in the diary are described in the 
efficacy analyses section.
7.3.3
Duration/Study Day/Time
Study day will be calculated as the number of days from first dose of SP-102 TF or placebo 
 
injection.
x
date of event – date of first dose of SP-102 TF or placebo 
+ 1, for events on 
or after first dose 
x
date of event – date of first dose of SP-102 TF or placebo 
, for events before 
first dose.
For all time to event analyses, subjects not reporting the specified endpoint will be censored at the 
time that the subjects were last known not to have experienced the endpoint.  The last visit is a 
censoring event, and events that occur after the last visit will be disregarded in the statistical 
analysis. For all endpoints not encompassing death, all deaths will be treated as censoring events.  
In complex cases where the censoring time of the subject is uncertain, the case will be reviewed 


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by the Worldwide Clinical Trials (WCT) statistician and a censoring time will be assigned before
database lock.
7.3.4
Conventions for Missing and Partial Dates
All rules explained below for partial/missing dates will be followed unless contradicted by any
other data recorded on the electronic Case Report Form (eCRF).
All dates presented in the individual subject listings will be as recorded on the eCRF (i.e., not 
completed as per the below rules).
7.3.5
Missing/Partial Start/Stop Date of Adverse Events and Concomitant 
Medications
Missing and partial start and stop date will be imputed for analysis purposes as follows:
Partial or missing stop date will be imputed as follows:
x
If the stop date is completely missing and the event has resolved or the subject has stopped 
taking the concomitant medication, the stop date will be imputed as the date of the subject’s 
last clinic visit in the study.
x
If only the year is known, the stop date will be imputed as “31-Dec” of that year or as the 
date of the subject’s last clinic visit in the study if in the same year.
x
If the month and year are known, the stop date will be imputed as the last day of that month 
unless the stop date corresponds to the same month as the subject’s last clinic visit in which 
case the date of subject’s last clinic visit in the study will be used instead.
Missing start date will be imputed as follows:
x
If the stop date occurs on or after the index injection or the event/concomitant medication 
is ongoing, the start date will be imputed as the date of the index injection.
x
If the stop date occurs before the index injection, the start date of the event/concomitant 
medication will be imputed as the subject’s screening date or the stop date of the 
event/concomitant medication whichever the earlier.
Partial start date (year present, but month and day missing)
x
If the stop date occurs on or after the index injection or the event/concomitant medication 
is ongoing, and the year is the same as the year of index injection the start date will be 
imputed as the date of the index injection. If the year is different from the year of index 
injection “01-Jan” will be used.


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x
If the stop date occurs before the index injection, the start date of the event/concomitant 
medication will be imputed as the “01-Jan” of the same year.
Partial start date (month and year present, but day missing)
x
If the stop date occurs on or after the index injection or the event/concomitant medication 
is ongoing, the start date will be imputed as the first day of the same month and year unless 
this partial start date is in same month as the index injection in which case the date of index
injection will be used. 
x
If the stop date occurs before the index injection, the start date will be imputed as the first 
day of the month and year of the partial stop date.
7.3.6
Inexact Values
In the case where a laboratory parameter has result recorded as “> x”, ”≥ x”, “< x” or “≤ x”, a 
value of x will be used for analysis purposes.
7.3.7
Electrocardiogram Data
If more than one value is recorded at a time point for electrocardiogram (ECG) data recorded on a 
continuous scale, the integer of the mean value will be recorded. For overall interpretation if more 
than one value is recorded, the most severe (worst case) of the respective readings will be taken.
7.3.8
Unscheduled Visits
Only scheduled post-baseline laboratory and vital signs values will be tabulated. Post-baseline 
repeat/unscheduled (except for repeat injection visits) assessments will be disregarded, although 
these post-baseline assessments will be listed in the relevant appendices to the CSR.
Repeat injection visits maybe captured as unscheduled visits. All assessments carried out during a 
repeat injection visit will be included in the analysis.
7.3.9
Early Termination Assessments
Early Termination (ET) assessment for post-baseline efficacy, laboratory or vital sign data will be 
mapped to the End of Study (Week 24) visit.
7.3.10
Randomization Strata
As described in Section 6, randomization is stratified by study site. Furthermore, protocol 
indicates that analysis will include adjustment for study site. There are approximately 45 study
sites and it is likely that some of these study sites will have small number of subjects that are 


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included in the mITT population and thus could lead to unreliable treatment effects estimates and 
p-values.  With this, the study sites will be pooled by state and then by region. However, if a 
state has significantly large number of subjects (eg almost double) compared to the other regions, 
it will be considered as one of the final pooled sites. The resulting final pooled sites (referred to 
as ‘site’ from here on) are as follows:
 
7.4 Conventions
All data listings, summaries, figures and statistical analyses will be generated using SAS version 
9.4 or higher1.
Subjects will be randomized to 1 of 2 treatment groups (SP-102 or placebo) and will receive 
1 injection at Baseline (D1). After 4 weeks, an additional injection of SP-102 may be administered 
to all subjects regardless of the treatment they were originally randomized to.  Because of this, 
baseline, efficacy, and safety variables will be summarized in two ways.
The first will summarize data for the 2 randomized treatment groups for the primary analysis 
period.  Subjects will be analyzed in either the SP-102 or placebo treatment groups.  Baseline 
summaries and data for this first 4 weeks will be summarized using the following treatment 
columns. Only baseline data will have the overall column.
SP-102
Placebo
Overall
The second will classify subjects into 1 of 4 groups and will summarize data for the secondary 
analysis period.  These 4 groups include the following:
x
Subjects who receive only 1 SP-102 injection
x
Subjects who receive 2 SP-102 injections




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baseline data, the lower and upper 95% confidence limits for the mean for the individual treatments 
will be given.
Categorical variables will be summarized by presenting the frequency and percent. Percentages 
will be based on the number of non-missing observations or the subject population unless 
otherwise specified. For each variable, all categories will be shown. Zero frequencies (but not the 
percent) within a category will be presented.
7.4.1
Decimal Places
Decimal places for derived data described in Section 7.2 will be determined by the scale of 
measurement unless otherwise stated. No decimal places will be displayed if the smallest 
calculated value is ≥100; 1 decimal place will be displayed when the smallest value is within the 
interval (10, 100), with 10 being inclusive; 2 decimal places will be displayed when the smallest 
value is within (1, 10), with 1 being inclusive; and so on for even smaller scales of measurement. 
If derived data such as number of days or total score is an integer, then it will be presented with 
zero decimal places.
Means, medians and percentiles will be displayed to one more decimal place than the data,
dispersion statistics (e.g. standard deviation) will have two more decimal places, and the minimum 
and maximum will be displayed to the same number of decimal places as reported in the raw data. 
Percentages will be displayed with one decimal place. 
P-Values will be quoted to 3 decimal places. P-values <0.001 will be presented as p<0.001. If this 
value is less than 0.05, 0.01 or 0.001, attention will be drawn to this fact using the conventional 
“*”, “**” or “***” annotation, respectively. 
7.5 Subject Disposition
Subject disposition will be summarized as follows:
x
The number of subjects randomized, and number in each analysis population (Safety, 
mITT, and Per Protocol) will be summarized by treatment group and overall based on all 
randomized subjects for both the primary and secondary analysis periods.
x
The number of subjects screened, who failed screening and the reasons for failure will be 
summarized using the Screened Population.
x
The number of early termination and the reasons for termination will be tabulated by 
treatment group and overall for each analysis period for the Safety Analysis Population.


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x
The number of subjects who are Primary Efficacy Endpoint Completers, 12-Week 
Completers, and 24week Completers will be summarized by treatment group and overall
for the Safety Analysis Population.
7.6 Protocol Deviations
Protocol deviations will be collected by study site and grouped into different categories, such as 
those who:
x
 
.
Major protocol violations that impact the primary efficacy analysis may lead to exclusion from the 
PP population.  Protocol deviation categories will be summarized for the safety analysis population 
by treatment group and overall. Protocol deviations will be summarized separately for the primary 
and secondary analysis periods.
A listing of protocol deviations will be provided within Appendix 16.2. 
7.7 Baseline Comparability
The comparability of treatment groups with respect to subject demographics and baseline 
characteristics will be assessed in a descriptive manner, but no formal statistical testing will be 
performed.
Standard continuous or categorical variable summaries will be presented by treatment group based 
on the Safety Analysis Population.
Baseline demographic data will be summarized using the Safety Analysis Population for both the 
primary and secondary analysis periods. This will include age in years, gender, fertility status 
(childbearing potential, post-menopausal, surgically sterile), ethnicity, race, height, weight, and 
BMI.
7.8 Medical History
Summary table of previous and ongoing conditions at screening will be presented by treatment 
group and overall for the Safety Analysis Population. Conditions will be presented by Medical 


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Dictionary of Regulated Activities (MedDRA) version 23.1 (or a more up-to-date version by the 
time of database lock) primary system organ class and preferred term. Listings of all medical 
history will be presented.
7.9 Prior and Concomitant Medications
Summary tables will be produced for prior and concomitant medications presented by treatment 
group and overall for the Safety Analysis Population. Prior medications are defined as all 
medications that started and stopped before the date of first dose of study drug. Prior medications 
will be summarized by the planned treatment for the first injection (SP-102, Placebo). 
Concomitant medication refers to all drugs and therapies that started prior to, on, or after the first 
dose of the study medication and ended on or after the date of the first dose of the study medication, 
or are ongoing at end of study. Medications are coded using WHODDE B3 Global - Sep 2019
Concomitant medications will be summarized using Anatomical Therapeutic Chemical [ATC]
Level 2. Listings of all prior and concomitant medications will be presented. Concomitant
medications will be summarized for each post randomization treatment period as follows:
x
First four weeks: summarizes all drugs and therapies taken within first 4 weeks after first 
dose of study medication. This will be tabulated using the two treatment groups: SP-102, 
Placebo.
x
Entire treatment period: summarizes all drugs and therapies that started prior to, on, or after 
the first dose of the study medication and ended on or after the date of the first dose of the 
study medication. This will be tabulated using the treatment group with four arms: SP-
102/SP-102, PBO/SP-102, SP-102/none, PBO/none.
x
Through 12 weeks: summarizes all drugs and therapies taken within first 12 weeks after 
first dose of study medication. This will be tabulated using the treatment group with four 
arms: SP-102/SP-102, PBO/SP-102, SP-102/none, PBO/none, and by exposure to SP-102,
that is, Exposed vs. Not Exposed to SP-102. The Exposed group will include the subjects 
that have received SP-102 for index injection and/or have repeat injection while Non-
Exposed group will include the subjects that have received Placebo for index injection and 
do not have repeat injection
7.10 Exposure to Study Drug
The number of randomized subjects that received index injection, that received repeat injection, 
and that received any injection will be summarized by treatment group.














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x
SP-102/SP-102 vs. PBO/none
x
SP-102/none vs. PBO/SP-102
x
SP-102/SP-102 vs. PBO/SP-102
A summary of the assessments at Weeks 16, 20, and 24 will be presented.
7.12.6.2
The time (days) to repeat injection of SP-102
The time to repeat injection of SP-102 will be analyzed using survival analysis methods. Subjects 
that do not receive a repeat injection will be censored at 20 weeks, and subjects who discontinue 
the study prior to 20 weeks without receiving a repeat injection will be censored at the time of 
discontinuation. The Kaplan-Meier estimator will be used to estimate the quartiles of the time to 
repeat injection in days. A Cox proportional hazards model will be utilized to test the treatment 
difference in time to repeat injection while adjusting for site, and Pain Catastrophizing Scale. The 
response variable of the Cox model will be time to repeat injection. The treatment group categories 
for this analysis will be the SP-102 and placebo groups. The quartiles and their corresponding 95% 
CIs from the Kaplan-Meier estimation, and the hazard ratio of SP-102 to placebo with its 95% CI
and p-value will be presented. A survival plot of time to repeat injection will also be presented. 
Listings of time to repeat injection will be presented.
7.12.6.3
Proportion of subjects receiving repeat injection.
The proportion of subjects receiving repeat injections will be compared between the two treatment 
groups using a Chi-Square test. The proportion of subjects receiving a repeat injection will be 
summarized by treatment group. 
7.12.6.4
The mean change from Baseline (D1) to Week 2, Week 4, Week 8, and 
Week 12 in the mean NPRS average pain score in the affected leg.
Baseline and post-baseline values for this endpoint is obtained as discussed in Section 7.12.1. A
similar approach in modeling the restricted maximum likelihood (REML)-based MMRM as in the 
primary analysis will be applied for this endpoint. Mean change from baseline to Week 2 and 
Week 4 will be analyzed and presented by the treatment received for the first injection (SP-102, 
Placebo). Mean change from baseline for the first 12 weeks (Weeks 2, 4, 8, and 12) will utilize 
similar MMRM model except that the outcome variable will be change from baseline in mean 
weekly NPRS average pain score in the affected leg at Weeks 2, 4, 8, and 12, and the fixed effects 
are as follows: treatment (four groups: SP-102/SP-102, PBO/SP-102, SP-102/none, PBO/none ),
week (2, 4, 8, 12), site, Pain Catastrophizing Scale group (<30 or ≥30), baseline averaged daily leg 




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x
SP-102/SP-102 vs. PBO/none
x
SP-102/none vs. PBO/SP-102
x
SP-102/SP-102 vs. PBO/SP-102
NPRS worst pain score is also collected at visits after Week 12 (Weeks 16, 20, and 24), but this 
score is only collected once, that is, during the clinic visits. This data will not be included in the 
model but will be included in the summary table.
7.12.6.6
The mean change from Baseline (D1) to Week 2, Week 4, Week 8, and 
Week 12 in the mean NPRS current pain score in the affected leg
The current pain intensity “pain now” is measured at every clinic visit and used for assessment of 
accuracy of pain reporting and monitoring of outlier values. This endpoint will be analyzed and 
presented using the same MMRM model described in the primary analysis but the response 
variable will be change from baseline in mean NPRS current pain score at Weeks 2, 4, 8, and 12;
with baseline NPRS score as the last score collected prior to the first injection on D1. Mean change 
from baseline to Week 2 and Week 4 will be analyzed and presented by the treatment received for 
the first injection (SP-102, Placebo). Mean change from baseline for the first 12 weeks (Weeks 2,
4, 8, and 12) will be analyzed and summarized by treatment received for second injection (SP-
102/SP-102, PBO/SP-102, SP-102/none, PBO/none). As part of this analysis, comparisons will 
test the mean LS mean differences between the following groups:
x
SP-102/none vs. PBO/none
x
SP-102/SP-102 vs. PBO/none
x
SP-102/none vs. PBO/SP-102
x
SP-102/SP-102 vs. PBO/SP-102
NPRS average scores are also collected at visits (Weeks 16, 20, and 24) after visit 12. This data 
will not be included in the model but will be included in the summary table.
7.12.6.7
The mean change from Baseline (D1) in the ODI total score to Week 12.
The treatment group categories will be: SP-102/SP-102, PBO/SP-102, SP-102/none, PBO/none.
As part of this analysis, comparisons will test the mean LS mean differences between the following 
groups:
x
SP-102/none vs. PBO/none




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Change from baseline to Week 12 will also be analyzed using an MMRM analysis with change 
from baseline to Week 12 (Weeks 4 and 12) as the response variable, with fixed effects for
treatment 
(SP-102/SP-102,
PBO/SP-102,
SP-102/none, PBO/none)
week,
site, Pain 
Catastrophizing Scale group (<30 or ≥30), baseline score, and treatment-by-week interaction. As
part of this analysis, comparisons will test the mean LS mean differences between the following 
groups:
x
SP-102/none vs. PBO/none
x
SP-102/SP-102 vs. PBO/none
x
SP-102/none vs. PBO/SP-102
x
SP-102/SP-102 vs. PBO/SP-102
PainDETECT will be summarized for Week 24 by treatment (four groups).
7.12.6.9
The mean change in BPI-SF score from Baseline (D1) to Week 4 and 
Week 12.
The BPI-SF is a 15-item self-rating scale assessing use of medications, as well as sensory, and 
reactive components of pain.  The BPI-SF includes items that will address components of sensory 
pain, including severity, location, chronicity, and degree of relief due to therapy.  The BPI-SF also 
has items that address reactive pain components, including depression, suffering, and perceived 
availability of relief. The BPI-SF will be collected at Screening, Baseline (D1), Week 4 (Day 29), 
and Week 12 visits. Two BFI-SF scales will be derived from the BRI-SF responses: Pain Severity 
Score and Pain Interference Score.
Pain Severity Score = Mean of items 3-6 (pain at its worst, pain at its least, average).
Pain Interference Score = Mean of items 9A-9G (interference of pain with: general activity, mood, 
walking, normal work, relations, sleep, enjoyment of life).
BPI-SF at Week 4 will be analyzed using an ANCOVA model with change from baseline at Week 
4 as the response variable with fixed effects for treatment (two groups: SP102 or placebo), site, 
Pain Catastrophizing Scale group (<30 or ≥30), and baseline score. Baseline BPI-SF scale score is
defined as the last BPI-SF assessment scale score prior to first injection on Day 1.
Change from baseline to Week 12 will also be analyzed using an MMRM analysis with change 
from baseline to Week 12 (Weeks 4 and 12) as the response variables, with fixed effects for 


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treatment (SP-102/SP-102,
PBO/SP-102,
SP-102/none, PBO/none),
week, site, Pain 
Catastrophizing Scale group (<30 or ≥30), baseline score, and treatment-by-week interaction. As
part of this analysis, post-hoc comparisons will test the mean LS mean differences between the 
following groups:
x
SP-102/none vs. PBO/none
x
SP-102/SP-102 vs. PBO/none
x
SP-102/none vs. PBO/SP-102
x
SP-102/SP-102 vs. PBO/SP-102
BPI-SF scores will be summarized for Week 24 by treatment (four groups).
7.12.6.10
Proportion of subjects achieving a response of 30%, 50%, and 75% 
reductions from Baseline (D1) in mean NPRS average pain score in the affected leg at 
Week 2 and Week 4.
Responders are defined and calculated as follows:
30% responder = (Change from baseline/ baseline) x 100 ≤-30.
50% responder = (Change from baseline/ baseline) x 100 ≤-50.
75% responder = (Change from baseline/ baseline) x 100 ≤-75.
Subjects that discontinue or have missing scores at Week 2 and Week 4 will be considered non-
responders.
The proportion of subjects achieving a response will be analyzed for each cut off percentage (30%, 
50%, and 75%) by week. This will be analyzed using a Chi-Square test where the p-value of the 
treatment difference will be presented. For each cutoff response percentage, a logistic regression 
models with treatment (two groups: SP102 or placebo), site, Pain Catastrophizing Scale group 
(<30 or ≥30), and baseline averaged daily leg pain score as factors will also be used to compare 
the treatment groups at each week. The odds ratio of SP-102 vs placebo, its corresponding 95% CI
and p-value will be presented. The number and percentage of responders will be presented for each 
visit.
A continuous responder analysis will also be performed. The proportion of subjects achieving a 
reduction in pain will be plotted against the continuous cutoff ranging from 0% to 100% reduction 
in pain intensity from Baseline (D1) as measured by the NPRS average daily leg pain scores in the 


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affected leg. This analysis will be performed using data observed at Week 4 and then over the first 
4 weeks (using average of the 4 weekly mean NPRS average daily leg pain scores in the affected 
leg to calculate the percent reduction). All subjects who withdraw early from the study within 4 
weeks will be considered non-responders. Treatment groups (SP-102 and placebo) will be 
compared using a log rank test.
7.12.6.11
The mean change from Baseline (D1) to Week 2, Week 4, Week 8, and Week 
12 in mean NPRS average pain score in the lower back. 
The average pain score in the lower back is measured at every clinic visit. This endpoint will be 
analyzed and presented using the same MMRM model described in the primary analysis but the 
response variable will be change from baseline in mean NPRS average pain score in the lower 
back at Weeks 2, 4, 8, and 12; with baseline NPRS score as the last score collected prior to the 
first injection on D1. Mean change from baseline for the first 4 weeks (Week 2 and Week 4) will 
be analyzed and presented by the treatment received for the first injection (SP-102, Placebo). Mean 
change from baseline for the first 12 weeks (Weeks 2, 4, 8, and 12) will also be analyzed and 
summarized by treatment received for second injection (SP-102/SP-102, PBO/SP-102, SP-
102/none, PBO/none). As part of this analysis, comparisons will test the mean LS mean differences 
between the following groups:
x
SP-102/none vs. PBO/none
x
SP-102/SP-102 vs. PBO/none
x
SP-102/none vs. PBO/SP-102
x
SP-102/SP-102 vs. PBO/SP-102
NPRS average scores are also collected at visits (Weeks 16, 20, and 24) after visit 12. This data 
will not be included in the model but will be included in the summary table.
7.12.6.12
CGIC at Week 2, Week 4, Week 8, and Week 12.
The CGIC is an 8-point scale (0 to 7, where 0 is not assessed, 1 is very much improved, and 7 is 
very much worse) that allows clinicians to rate the subject’s global impression of change.  CGIC 
will be collected after randomization at Weeks 2, 4, 8, 12, 16, 20, and 24.  For analysis, a subject 
will be classified as either CGIC responder, that is, a CGIC response of 1: very much improved or 
2: much improved or a CGIC non-responder, that is, all other CGIC responses (recorded as 3-7
in the scale).  Subjects who do not complete the measure at the timepoint of interest will also be 
considered non-responders. The number and percentage of subjects reporting each of the seven


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CGIC response levels will also be summarized by visit and treatment. Analyses will utilize
separate Chi-Square tests for Week 2 and Week 4 where the p-value of the treatment difference 
will be presented. Separate logistic regression models with treatment, site, and Pain 
Catastrophizing Scale group (<30 or ≥30) as factors will also be used to compare the treatment 
groups for Week 2 and Week 4 using the 2 treatment groups. The odds ratio of SP-102 vs placebo
at Weeks 2 and 4, and its corresponding 95% CI and p-value will be presented. Listings of CGIC 
will also be provided.
Separate Chi-Square tests and similar logistic regression analyses will be applied at Weeks 2, 4, 8, 
and 12 using the treatment group with four arms: SP-102/SP-102, PBO/SP-102, SP-102/none,
PBO/none. The following odds ratios at Weeks 2, 4, 8, and 12 and the corresponding 95% CIs and 
p-values will be presented:
x
SP-102/none vs. PBO/none
x
SP-102/SP-102 vs. PBO/none
x
SP-102/none vs. PBO/SP-102
x
SP-102/SP-102 vs. PBO/SP-102
A summary of the assessments at Weeks 16, 20, and 24 will be presented.
7.12.6.13
Cumulative use of rescue medication (mg of acetaminophen)
In this study, acetaminophen is the permitted and study-provided rescue medication. For subjects 
that withdraw early, their missing weekly values after withdrawal will be imputed using the 
average weekly score for the respective treatment group. If the subject has partial records of rescue 
medication on the week of subject’s withdrawal, the rescue medication use on that week will be 
imputed as follows:
[ partial record of rescue medication on the withdrawal week * (7/number of days in the withdrawal 
week with partial record) ]. 
Cumulative use of rescue medication at Week 4 will be obtained as the rescue medication use 
during the first four weeks relative to the index injection, that is, up to the subject’s Day 29 in the 
study. It will be analyzed using an analysis of variance (ANOVA) model with cumulative use from 
baseline to Week 4 as the response variable with fixed effects for treatment (two groups: SP102 or 
placebo), site, and Pain Catastrophizing Scale group (<30 or ≥30). The same ANOVA model will 


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be applied on only subjects that complete 4 Weeks and output will be presented using the two 
treatment groups.
Cumulative use of rescue medication at Week 12 will be obtained as the rescue medication use 
during the first 12 weeks relative to the index injection, that is, up to subject’s Day 85 in the study. 
It will also be analyzed using an ANOVA model with cumulative use from baseline to Week 12 
as the response variable with fixed effects using the four treatment (SP-102/SP-102, PBO/SP-102, 
SP-102/none, PBO/none) variable, site, and Pain Catastrophizing Scale group (<30 or ≥30). The 
same ANOVA model will be applied on only subjects that complete 12 Weeks and output will be 
presented using the four treatment groups.
7.12.6.14
Time to first rescue medication dose
The time to first rescue medication dose, in days, will be analyzed like the time to event endpoint 
in Section 7.11.6.2. Time to first rescue medication dose will be analyzed separately for the first 
4 weeks (two groups), and the first 12 weeks (four groups). For both analysis periods, time to 
first rescue medication dose will be calculated relative to the date of index injection. For the 
primary analysis period (first 4 weeks), subjects who do not use rescue medications for the first 4 
weeks will be censored at Day 29th while subjects who discontinue the study prior to the
subject’s Day 29th in the study will be censored at the time of discontinuation. Similarly, for the 
secondary analysis period, subjects who do not use rescue medication for the first 12 weeks will 
be censored at Day 85th while subjects who discontinue the study prior to the subject’s Day 85th
in the study will be censored at the time of discontinuation.
7.12.6.15
Proportion of subjects requiring rescue medication
The proportion of subjects requiring rescue medications will be compared across treatment arms 
using a Chi-Square test. This endpoint will be analyzed separately for the first 4 weeks (two 
groups), and the first 12 weeks (four groups).
7.12.6.16
Percent of rescue medication free days.
The percent of rescue medication free days will be calculated for the primary efficacy endpoint 
completers as:
୒୳୫ୠୣ୰ ୭୤ ୢୟ୷ୱ ୵୧୲୦୭୳୲ ୰ୣୱୡ୳ୣ ୫ୣୢ୧ୡୟ୲୧୭୬ ୤୰୭୫ ୠୟୱୣ୪୧୬ୣ ୲୭  ୱ୳ୠ୨ୣୡ୲ᇲୱ ୈୟ୷ ଶଽ୲୦ ୧୬ ୲୦ୣ ୱ୲୳ୢ୷ 
ଶ଼
 x 100
For subjects that withdrew from the study prior to the subject’s Day 29th in the study, the percent 
of rescue medication free days will be calculated as:


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୒୳୫ୠୣ୰ ୭୤ ୢୟ୷ୱ ୵୧୲୦୭୳୲ ୰ୣୱୡ୳ୣ ୫ୣୢ୧ୡୟ୲୧୭୬ ୤୰୭୫ ୠୟୱୣ୪୧୬ୣ ୲୭ ୉ୟ୰୪୷ ୘ୣ୰୫୧୬ୟ୲୧୭୬ ୈୟ୲ୣ      
ே௨௠௕௘௥ ௢௙ ௗ௔௬௦ ௙௥௢௠ ௕௔௦௘௟௜௡௘ ௧௢ ா௔௥௟௬ ்௘௥௠௜௡௔௧௜௢௡ ஽௔௧௘
 x 100
This will be analyzed for the primary analysis period. A one-way ANOVA model will be used to 
test the difference between SP-102 and the placebo arms.
7.12.6.17
The mean change from Baseline (D1) to Week 2, Week 4, Week 8, and Week 
12 in the mean morning (AM) NPRS average pain score in the affected leg
This will be analyzed and presented using the same MMRM model described in the primary 
analysis, but the response variable will be change from baseline in mean weekly morning (AM) 
NPRS average pain score. Baseline morning NPRS average pain score is the mean of at least 5 
days and no more than 7 days of morning NPRS average pain scores from the Screening visit 
until treatment randomization (D1). The mean weekly morning NPRS average pain score will be 
calculated by taking the average of the daily morning NPRS average pain scores of the seven 
days prior to that week. Post-baseline mean weekly morning NPRS average pain scores will be 
calculated as long as a week has at least 3 days with morning NPRS average pain score.  If there 
are less than three days with morning NPRS average pain score, the mean weekly morning 
NPRS score will be set to missing. The mean weekly morning NPRS score will be calculated for 
each subject for each week up to Week 12. Change from baseline in mean weekly morning 
NPRS score will be calculated by subtracting the baseline value from the weekly morning NPRS
score. Mean change from baseline for the first 4 weeks (with overall average) will be analyzed 
and presented by the treatment received for the first injection (SP-102, Placebo). Mean change 
from baseline for the first 12 weeks (Weeks 2, 4, 8, and 12) will be analyzed and summarized by 
treatment received for second injection (SP-102/SP-102, PBO/SP-102, SP-102/none, PBO/none).
As part of this analysis, comparisons will test the mean LS mean differences between the 
following groups;
x
SP-102/none vs. PBO/none
x
SP-102/SP-102 vs. PBO/none
x
SP-102/none vs. PBO/SP-102
x
SP-102/SP-102 vs. PBO/SP-102


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7.12.6.18
The mean change from Baseline (D1) to Week 2, Week 4, Week 8, and Week 
12 in the mean evening (PM) NPRS average pain score in the affected leg
This will be analyzed and presented using the same MMRM model described in the primary 
analysis, but the response variable will be change from baseline in mean weekly evening (PM) 
NPRS average pain score. Baseline evening NPRS average pain score is the mean of at least 5 
days and no more than 7 days of evening NPRS average pain scores from the Screening visit 
until treatment randomization (D1). The mean weekly evening NPRS average pain score will be 
calculated by taking the average of the daily evening NPRS average pain scores of the seven 
days prior to that week. Post-baseline mean weekly evening NPRS average pain scores will be 
calculated as long as a week has at least 3 days with evening NPRS average pain score.  If there 
are less than three days with evening NPRS average pain score, the mean weekly evening NPRS 
score will be set to missing. The mean weekly evening NPRS score will be calculated for each 
subject for each week up to Week 12. Change from baseline in mean weekly evening NPRS 
score will be calculated by subtracting the baseline value from the weekly evening NPRS score. 
Mean change from baseline for the first 4 weeks (with overall average) will be analyzed and 
presented by the treatment received for the first injection (SP-102, Placebo). Mean change from 
baseline for the first 12 weeks (Weeks 2, 4, 8, and 12) will be analyzed and summarized by 
treatment received for second injection (SP-102/SP-102, PBO/SP-102, SP-102/none, PBO/none).
As part of this analysis, comparisons will test the mean LS mean differences between the 
following groups;
x
SP-102/none vs. PBO/none
x
SP-102/SP-102 vs. PBO/none
x
SP-102/none vs. PBO/SP-102
x
SP-102/SP-102 vs. PBO/SP-102
7.12.6.19
Multiplicity
To control for multiplicity, a sequential testing procedure will be used on the key secondary and 
other secondary endpoints.  Thus, if the primary endpoint is statistically significant, then the key 
secondary endpoint can be tested.  Then if the key secondary endpoint is statistically significant,
then the next secondary endpoint can be tested.  This will continue until all endpoints have been 
tested, or until non-significance is observed for an endpoint.  The ordering of the tests will follow 
the order the endpoints listed below:


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7.12.6.20
Placebo Responder Analysis
An analysis predicting the placebo response may be performed. Full details will be provided in a 
separate SAP. 
7.13 Safety Analyses
The safety analyses will be presented in two ways:
1) by the two treatment groups received in the first four weeks for the primary analysis 
period
2) by the four treatment groups for the data up to 24 weeks for the secondary analysis period
All safety analyses will be done in the Safety Analysis Population.
7.13.1
Adverse Events
Adverse events will be recorded using MedDRA v23.1 or a more up-to-date version by the time 
of database lock. A treatment emergent adverse event (TEAE) is defined as:
x
Any AE that has an onset on or after the first dose of SP-102 or placebo
x
Any pre-existing AE that has worsened in severity on or after the first dose of SP-102 or
placebo.
A treatment-related TEAE is any study medication related TEAE and/or study procedure related 
TEAE.
A study medication treatment-related AE is defined as one of the following; possibly related,
probably related, or definitely related to the study drug. If an AE has a missing relationship to
study medication it is assumed to be related to the study drug for analysis purposes.
A study procedure treatment-related AE is defined as an AE related to the study procedure.
The intensity/standard toxicity grade of an AE is defined as an AE being Grade 1 (Mild), Grade 2 
(Moderate), Grade 3 (Severe), or Grade 4 (Life-Threatening).


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Severe intensity (Grade 3) will be assumed for an AE with missing intensity.
The summary of TEAEs will include the total number and percentage of subjects reporting an 
event.  In counting the number of events reported, a continuous event, i.e. reported more than once 
and which did not cease, will be counted only once; non-continuous AEs reported several times 
by the same subject will be counted as multiple events.
TEAEs will be assigned to one of the two treatments (SP-102 or Placebo). AEs starting while on 
Placebo but before the repeat injection will be assigned to Placebo. AEs starting on or after the 
repeat injection of SP-102 will be assigned to SP-102. Any pre-existing TEAE that started during 
the Placebo use and that has worsened in severity on or after the repeat injection of SP-102 will be 
assigned to SP-102.
Any TEAEs will be summarized by treatment, for each post-randomization treatment period:
x
Entire treatment period
x
Occurring after the randomization injection, but prior to a second injection (of SP-102)
x
Occurring after the second injection (of SP-102)
The following incidence (number and percent of subjects reporting the AE at least once during the 
study) of TEAEs tables will be presented:
x
Overall incidence and the number of TEAEs, related TEAEs, serious adverse events 
(SAEs), related SAEs, TEAEs leading to withdrawal, and TEAEs leading to death.
x
TEAE by system organ class and preferred term, incidence and number of events
x
Study medication-related TEAE by system organ class and preferred term, incidence and 
number of events
x
Study procedure-related TEAE by system organ class and preferred term, incidence and 
number of events
x
Serious TEAE by system organ class and preferred term, incidence and number of events
x
Serious study medication-related TEAE by system organ class and preferred term, 
incidence and number of events
x
Serious study procedure-related TEAE by system organ class and preferred term, incidence 
and number of events
x
TEAE by system organ class, preferred term and intensity, incidence
x
Serious TEAE by system organ class, preferred term and intensity, incidence
x
Treatment-related TEAE by system organ class, preferred term and intensity, incidence


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x
TEAEs leading to early termination of the study by system organ class and preferred term, 
incidence
x
Listing of Serious TEAEs (presented in the Table section of the appendices)
x
Listing of Deaths (presented in the Table section of the appendices)
Additionally, an overall summary of the incidence and the number of TEAEs, related TEAEs, 
SAEs, related SAEs, TEAEs leading to withdrawal, and TEAEs leading to death through 12 weeks,
and a summary of incidence and number of events of TEAEs by system organ class and preferred 
term through 12 weeks will be presented as follows:
x
by four groups (SP-102/SP-102, PBO/SP-102, SP-102/none, and PBO/none)
x
by treatment (Placebo, SP-102) but only for the subjects in the PBO/SP-102 group
x
by exposure to SP-102, that is, Exposed vs. Not Exposed to SP-102; the Exposed group 
will include the subjects that have received SP-102 for the index injection and/or have a
repeat injection while Non-Exposed group will include the subjects that have received
Placebo for the index injection and do not have repeat injection
All AEs will be listed.
7.13.2
Laboratory Data
Descriptive statistics of the observed values and change from baseline (continuous data) will be 
presented by treatment group and visit for each hematology (hemoglobin, hematocrit, red blood 
cell count, white blood cell (WBC) count (with differential [lymphocytes, neutrophils, eosinophils, 
basophils, and monocytes]), platelet count, hemoglobin A1c, activated partial thromboplastin time, 
prothrombin time and international normalization ratio), urinalysis (color, turbidity, specific 
gravity, pH, glucose, protein, ketones, urobilinogen, bilirubin, blood nitrate, leukocyte esterase, 
and microscopic examination) and serum chemistry (albumin, alanine aminotransferase [ALT],
alkaline phosphatase, aspartate aminotransferase [AST], direct bilirubin, total bilirubin, blood urea 
nitrogen, calcium, chloride, creatine kinase, creatinine, gamma-glutamyl transferase, glucose, 
lactate dehydrogenase, potassium, sodium, uric acid) parameter. Each measurement (continuous 
data) will be classed as below, within, or above normal range, based on ranges supplied by the 
laboratory used. Laboratory data will be summarized for the secondary analysis period.
Shift tables in relation to the normal range from baseline to each follow-up visit will be presented.
All other laboratory tests will be listed only. This includes troponin I, troponin T, lipid panel, 
plasma cortisol, human immunodeficiency virus (HIV), hepatitis B, hepatitis C, and serum 


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pregnancy test (females of childbearing potential only), cortisol, urine drug screen, and urine 
pregnancy test.
A listing of abnormal laboratory measurements defined as any out of normal range laboratory 
values recorded throughout the study will be presented.
7.13.3
Vital Signs
Descriptive statistics for observed values and changes from baseline in the following vital signs 
will be presented by treatment group, visit, and timepoint within visit:
x
Systolic blood pressure (mmHg)
x
Diastolic blood pressure (mmHg)
x
Pulse rate (Heart Rate) [bpm]
Vital signs data will be summarized separately for both the primary and the secondary analysis 
periods. Vital sign values will be categorized into the following potential clinical concern 
categories if applicable, and then summarized.
Vital Sign 
Potential Clinical Concern Categories 
Systolic blood pressure
≥160 mmHg
Diastolic blood pressure
≥100 mmHg
Pulse rate (Heart Rate)
<60 or >100 bpm
All vital sign measurements including the position of the subject when the measurement was 
taken will be listed.
7.13.4
Electrocardiogram Data
Descriptive statistics for observed values in the following ECG variables at the screening visit
will be tabulated:
x
Pulse Rate (Heart rate) [bpm]
x
PR interval (ms)
x
RR interval (ms)
x
QRS duration (ms)  
x
QT interval (ms) 
x
QTc interval (ms) [Bazett’s formula - QTcB] 
x
QTc interval (ms) [Fridericia’s formula - QTcF] 


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All ECG measurements and the position of the subject when the measurement was taken will be 
listed.
7.13.5
Physical Examination
The body systems within the physical examination data at Screening will be summarized by 
treatment group and finding (Normal, Abnormal NCS, Abnormal CS). Details of clinically 
significant findings will be listed. 
7.13.6
Neurological Examination
Neurological examination will include evaluation of mental status (awareness of person, place, 
and time), cranial nerves, motor function and balance, sensory exam (ability to feel) and reflexes. 
Specific neurological examination demonstrating findings of radiculopathy, including straight leg 
raise test will be performed as part of this evaluation, according to the checklist (see Appendix A
of the protocol).
Shift tables in relation to finding (Normal, Abnormal) from baseline to each follow-up visit will 
be presented for the General Neurological Exam results. Details of any abnormalities will be 
listed.
8
INTERIM ANALYSIS
No interim analyses are planned.
9
DATA SAFETY MONITORING BOARD ANALYSIS
No data safety monitoring board (DSMB) analyses are planned.
10 POST-HOC ANALYSIS
Sensitivity Analyses to assess impact of COVID-19 on study endpoints might be considered and 
will be done as post-hoc analyses.
11 CHANGES TO PLANNED PROTOCOL ANALYSIS
The following are changes to the planned protocol analysis:
x
 
 
 


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x
A Screened Population, which consists of subjects that signed the informed consent form 
and were assigned a user subject number, was added.
x
A 12-week Completer, defined as one who receives an injection of study drug and 
completes the study through Week 12, is added as another type of completer in this trial. 
x
The following endpoints were updated:
1. “Week 4” was added to the endpoint “The mean change from Baseline (Day 1) to 
Week 2, Week 8, and Week 12 NPRS mean average pain score in the affected leg”.
The updated endpoint is “The mean change from Baseline (Day 1) to Week 2, Week 
4, Week 8, and Week 12 NPRS mean average pain score in the affected leg”. 
2. “during the first 4 weeks” was removed from the endpoint “Proportion of subjects 
requiring rescue medications during the first 4 weeks”. The updated endpoint is 
“Proportion of subjects requiring rescue medications”.
x
Percent of rescue medication free days, mean change from Baseline (D1) to Week 4 in 
the mean morning (AM) NPRS average pain score in the affected leg, and mean change 
from Baseline (D1) to Week 4 in the mean evening (PM) NPRS average pain score in the 
affected leg were added as endpoints.
x
Ordering of the endpoints to be tested for controlling for multiplicity has changed. PGIC 
which was 13th in the order of endpoints in the protocol was moved to third in order. 
That is, PGIC will be tested next if the key secondary endpoint is statistically significant.   
x
 
 
x
An overall summary of the incidence and the number of TEAEs, related TEAEs, SAEs, 
related SAEs, TEAEs leading to withdrawal, and TEAEs leading to death through 12 
weeks and a summary of incidence and number of events of TEAEs by system organ 
class and preferred term will also be summarized as follows:
-
by four groups (SP-102/SP-102, PBO/SP-102, SP-102/none, and PBO/none)
-
by treatment (Placebo, SP-102) but only for the subjects in the PBO/SP-102 group
-
by exposure to SP-102, that is, Exposed vs. Not Exposed to SP-102; the Exposed 
group will include the subjects that have received SP-102 for the index injection 


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and/or have a repeat injection while Non-Exposed group will include the subjects 
that have received Placebo for the index injection and do not have repeat injection
x
The Primary Efficacy Endpoint Completer definition was changed from “as one who 
receives an injection of study drug and completes the study though W4” to “as one 
who receives an index injection and who has enough data to calculate data for the 
primary analysis period (i.e. first four weeks) regardless if Week 4 visit was completed
or not”


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12 REFERENCES
1. SAS Institute Inc.  The SAS System, Version 9.4. Cary, NC, SAS Institute Inc. 2012.
2. Yuan, Y. (2014). Sensitivity Analysis in Multiple Imputation for Missing Data. SAS
Global Forum 2014 Conference. Retrieved from 
http://support.sas.com/resources/papers/proceedings14/SAS270-2014.pdf
3. Li, L. (2019). SAS® V9. 4 MNAR statement for multiple imputations for missing not at 
random in longitudinal clinical trials. PharmaSUG 2019 Conference. Retrieved from 
https://www.pharmasug.org/proceedings/2019/ST/PharmaSUG-2019-ST-103.pdf
4. Fairbank JC, Pynsent PB. The Oswestry Disability Index. Spine 2000 Nov
15;25(22):2940-52