Corticosteroid Lumbar Epidural Analgesia for Radiculopathy (C.L.E.A.R.)
Phase: PHASE3
Conditions: Lumbosacral Radicular Pain
Sponsor: Scilex Pharmaceuticals, Inc.



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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