Clinical trial NCT03613662
Conditions: Lumbosacral Radicular Pain
Keywords: lumbosacral radicular pain sciatica leg pain
Sponsor: Semnur Pharmaceuticals, Inc.
Start date: 2018-07-13; Completion date: 2019-03-15
Enrollment: 19 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This is an open-label, single-arm, repeat dose study to characterize the pharmacodynamics and safety/tolerability of SP-102 administered by epidural injection.

Detailed description:

Arms: arm 1: SP-102
Interventions: intervention 1: SP-102
Intervention descriptions: intervention 1: Injection

Protocol documents:
Prot_000.pdf: 
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Protocol Title: 
An Open-label, Single-arm Study to Characterize 
the Pharmacodynamics and Safety of Repeat 
Dose SP-102 (Dexamethasone Sodium Phosphate 
Injectable Gel) Administered by Epidural 
Injection in Subjects with Lumbosacral 
Radiculopathy 
Protocol Number: 
SP-102-03 
Clinical Phase: 
2 
Protocol Version and Date: 
Version 1.0, 08 Jun 2018 
US Investigational New 
Drug Number: 
 
Sponsor: 
Semnur Pharmaceuticals, Inc. 
301 N. Whisman Rd, Suite 100 
Mountain View, CA 94043 
 
-CONFIDENTIAL- 
This document and its contents are the property of and confidential to Semnur Pharmaceuticals, 
Inc.  Any unauthorized copying or use of this document is prohibited. 
 
 
 
 




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SYNOPSIS 
Protocol Title: 
An Open-label, Single-arm Study to Characterize the Pharmacodynamics and 
Safety of Repeat Dose SP-102 (Dexamethasone Sodium Phosphate Injectable Gel) 
Administered by Epidural Injection in Subjects with Lumbosacral Radiculopathy 
Protocol Number: 
SP-102-03 
Study Center(s):  
Up to 2 
Phase of Development: 
2 
Objectives: 
The primary objective of the study is to characterize repeat dose 
pharmacodynamics (PD) of SP-102 (10 mg dexamethasone) administered by 
epidural injection with respect to hypothalamic-pituitary-adrenal (HPA) 
suppression using plasma cortisol levels, white blood cell count (WBC), and blood 
glucose. 
The secondary objectives of the study are to: 
• 
Evaluate the safety and tolerability of single and repeat dose SP-102 
(10 mg dexamethasone) administered by epidural injection in subjects 
with lumbosacral radiculopathy. 
• 
Evaluate the analgesic effect on leg pain (as measured by the Numeric 
Pain Rating Scale [NPRS] in the affected leg) following the index 
(Treatment [T] 1) and repeat (T2) injections. 
Study Design: 
This is an open-label, single-arm, repeat dose study to characterize the PD and 
safety/tolerability of SP-102 (10 mg dexamethasone) administered by epidural 
injection as transforaminal (TF) or interlaminar (IL) injection under fluoroscopic 
guidance in subjects with lumbosacral radiculopathy.   
Subjects meeting the eligibility criteria will be enrolled in the study and receive a 
single 2-mL epidural injection of SP-102 (10 mg dexamethasone) in T1 (index 
injection) and T2 (repeat injection), separated by 4 to 8 weeks.  T2 will only be 
provided if a repeat injection is warranted and the subject continues to meet 
applicable study inclusion and exclusion criteria. 
Subjects who have been using opioids other than high dose opioids within 30 days 
prior to Screening (see Exclusion #12), may participate in the study if they agree to 
discontinue the opioid therapy prior to the Screening Visit and sign the 
pre-screening informed consent form.  
The study will include a 21-day screening period (Visit 1), sequential treatments 
periods T1 and T2, separated by 4 to 8 weeks; each treatment period will consist of 
a Baseline Visit (Day 0), SP-102 injection (Day 1), and a 4-week follow-up period.  
Screening, Baseline, and follow-up visits will occur at the research site.  Subjects 
will stay in a restricted environment 
) for each of 5 nights beginning the 
night before each injection to ensure fasting each evening and on-time collection of 
PD assessments each morning.  Subjects will be permitted to leave the restricted 
environment 
) and resume normal activities each day after study 
procedures are performed.  The SP-102 injection will be administered in an 
injection procedure facility.  Safety and PD assessments will be collected at 
Screening, pre-dose, daily for 4 days post dose during the stay in the restricted 
environment (
), and at 3 outpatient follow-up visits (on Day 8, Day 15, and 
Day 28) after each injection.  The end of study (EOS) visit (Visit 19) is the final 
outpatient visit after the second injection.  If the subject is not eligible for T2 or 
chooses to withdraw from further participation in the study, the subject will be 
scheduled for the EOS visit (Visit 19). 
From the time of informed consent to the EOS visit, each subject’s participation 
may last up to 15 weeks. 






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13. An epidural steroid injection for the treatment of the current episode of 
lumbosacral radicular pain during the 2 months prior to the Screening 
Visit.   
14. History of spine surgery prior to the Screening or Baseline Visit, which 
may interfere with IL epidural injection, or plans to undergo spine surgical 
intervention while in the study.   
15. Has donated blood exceeding 500 mL during the 45 days before Baseline 
Visit. 
16. Use of any investigational drug or device within 30 days prior to the 
Screening Visit or is scheduled to receive an investigational drug other 
than study drug during the course of this study.   
17. If female, are lactating/breastfeeding, plan to breastfeed, currently 
pregnant, or plan to become pregnant while participating in the study. 
18. Alcohol dependence, drug abuse, or drug addiction within 1 year of the 
Screening Visit. 
19. 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. 
20. The presence of any disorder, condition, laboratory abnormality, or 
circumstance (with the exception of the condition under study) as 
determined by a medical and psychiatric history, medical examination, 
electrocardiogram (ECG), serum chemistry, hematology, and urinalysis 
that, in the opinion of the investigator, has the potential to compromise 
subject safety, prevent study completion, and/or to have a confounding 
effect on outcome measures. 
Investigational Product: 
SP-102: dexamethasone sodium phosphate injectable gel, 10 mg dexamethasone 
Comparator Product: 
None 
Duration of Treatment: 
2 single injections of SP-102.  
Main Parameters to 
Measure 
Pharmacodynamics: 
The following PD assessments will be performed during the study: 
• 
Cortisol  
• 
Fasting blood glucose 
• 
WBC 
• 
NPRS measuring current, worst, and average leg and back pain 
• 
Brief Pain Inventory (BPI-SF)  
Main Parameters of 
Safety: 
The following safety assessments will be performed during the study: 
• 
Adverse events (AEs) 
• 
Vital signs  
• 
Body weight 
• 
Physical examinations  
• 
General neurological examination 
• 
Targeted neurological examination 
• 
12-lead ECGs  
• 
Clinical laboratory tests (serum chemistry, hematology, urinalysis, HIV, 
viral hepatitis screening, and coagulation tests) 
• 
Serum or urine pregnancy tests 


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Pharmacodynamic 
Endpoints: 
• 
Dexamethasone-induced HPA suppression as measured by: 
o 
Observed total blood cortisol levels, change from baseline 
cortisol levels, and percent change from baseline cortisol levels 
o 
Observed glucose levels, change from baseline glucose levels, 
and percent change from baseline glucose levels 
o 
Observed white blood cell counts, change from baseline white 
blood cell counts, and percent change from baseline white blood 
cell counts 
• 
NPRS (average leg pain and back pain) and BPI-SF  
• 
Change from T1 Day 0 and T2 Day 0 through Day 28 in NPRS (average 
leg pain and back pain) and BPI-SF over time following the index (T1) 
and repeat (T2) epidural injections, respectively  
• 
Percent change from T1 Day 0 and T2 Day 0 through Day 28 in NPRS 
(average leg pain and back pain) and BPI-SF following the index (T1) and 
repeat (T2) epidural injections, respectively 
Safety Endpoints: 
Safety endpoints are as follows: 
• 
Incidence of treatment-emergent AEs (TEAEs) and serious adverse events 
(SAEs)  
• 
Change from baseline in clinical laboratory parameters, vital sign 
measurements, ECG findings, and physical examination parameters 
following each treatment  
Statistical Analyses: 
No formal statistical power calculation was performed for this study; the sample 
size is based on clinical and practical considerations. 
TEAEs and SAEs, observed values and changes in clinical laboratory parameters, 
and vital signs will be summarized descriptively for each treatment.  Shifts in 
laboratory parameters, physical examination findings, general neurological 
examination findings, and targeted neurological examination findings will be 
summarized by treatment group. 
Unless otherwise specified, baseline is defined as the last non-missing 
measurement taken prior to treatments T1 or T2 (reference start date).  This 
includes screening or unscheduled assessments that would have been performed no 
earlier than 21 days before the reference start date. 
In the case where the last non-missing measurement and the reference start date 
coincide, that measurement will be considered pre-reference, but AEs and 
medications commencing on the reference start date will be considered 
post-reference. 
Cortisol levels, WBC counts, and fasting blood glucose levels (observed, change 
from baseline, and percent change from baseline) will be summarized by treatment 
and measurement time using descriptive statistics.  Dexamethasone-induced HPA 
suppression will be evaluated by using the observed total plasma cortisol level, 
glucose levels, and WBC count.  Other PD analyses may be performed as 
appropriate.  
For blood cortisol and glucose levels, and WBC counts (change‐from‐baseline), PD 
parameters, ie, area under the effect curve over 28 days (AUEC28 days) and 
maximum effect (Emax) following the T1 (index) and T2 (repeat) injections will be 
calculated.   
AUEC28 days is defined as the change from baseline (for cortisol, glucose, and 
WBC) and calculated using linear trapezoidal summation from pre-dose to Day 28 
in each treatment period.  Emax is the baseline-adjusted maximum increase in 


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glucose level and WBC count or the maximum decrease in cortisol levels over the 
28 days post dose in each treatment period.  
The PD parameters will be analyzed using a mixed model analysis of variance 
using PROC MIXED with a fixed effect for treatment and a random effect for 
subject.  Estimates and 90% confidence intervals (CIs) will be first constructed in 
the logarithmic scale.  By taking anti-logarithms, estimates and CIs for the 
geometric means and ratios of geometric means will be calculated.  All CIs will be 
2-sided.  
A lack of effect of repeat injection on the PD will be concluded if the 90% CIs for 
the ratio of T2 (repeat injection; Test) to T1 (index; Reference) for both 
AUEC28 days and Emax are completely contained within the range of 80 to 125%. 
The pain assessment closest to and prior to dosing in each treatment period will be 
used as baseline for each treatment period.  The following pain-score endpoints 
will be summarized over time by treatment using descriptive statistics: 
• 
NPRS (average leg pain and back pain) and BPI-SF  
• 
Change from T1 Day 0 and T2 Day 0 through Day 28 in NPRS (average 
leg pain and back pain) and BPI-SF over time following the index (T1) 
and repeat (T2) epidural injections, respectively  
• 
Percent change from T1 Day 0 and T2 Day 0 through Day 28 in NPRS 
(average leg pain and back pain) and BPI-SF following the index (T1) and 
repeat (T2) epidural injections, respectively 
 
 
 


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TABLE OF CONTENTS 
SIGNATURE PAGE .......................................................................................................................2 
SYNOPSIS .......................................................................................................................................3 
TABLE OF CONTENTS .................................................................................................................9 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ................................................14 
ADMINISTRATIVE STRUCTURE .............................................................................................17 
1 
INTRODUCTION .................................................................................................................18 
1.1 
Background ........................................................................................................................18 
1.1.1 Lumbosacral Radicular Pain ......................................................................................18 
1.1.2 Epidural Steroids ........................................................................................................18 
1.1.3 SP-102 ........................................................................................................................20 
1.2 
Preclinical Studies ..............................................................................................................20 
1.3 
Clinical Studies ..................................................................................................................21 
1.4 
Use of Epidural Injection of Dexamethasone for Radicular Pain in the Clinical Setting ..22 
1.5 
Study Rationale ..................................................................................................................22 
1.6 
Dose Rationale ...................................................................................................................22 
1.7 
Study Endpoint Rationale ..................................................................................................23 
1.8 
Risks and Benefits for Subjects .........................................................................................23 
2 
STUDY OBJECTIVES ..........................................................................................................24 
2.1 
Primary Objective ..............................................................................................................24 
2.2 
Secondary Objectives .........................................................................................................24 
3 
INVESTIGATIONAL PLAN ................................................................................................25 
3.1 
Overall Study Design and Plan ..........................................................................................25 
3.2 
Study Duration ...................................................................................................................26 
3.3 
Selection of Study Population ............................................................................................26 
3.3.1 Inclusion Criteria .......................................................................................................26 
3.3.1.1 
Treatment 1 Inclusion Criteria .......................................................................................... 26 
3.3.1.2 
Treatment 2 Inclusion Criteria .......................................................................................... 27 
3.3.2 Exclusion Criteria ......................................................................................................27 
3.3.3 Stopping Rules ...........................................................................................................29 
3.3.4 Removal of Subjects from Therapy or Assessment ...................................................29 


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3.4 
Treatments..........................................................................................................................30 
3.4.1 Details of Study Treatments .......................................................................................30 
3.4.2 Dosage Schedule ........................................................................................................30 
3.4.3 Treatment Assignment ...............................................................................................31 
3.4.4 Drug Packaging and Blinding ....................................................................................31 
3.4.5 Drug Inventory and Accountability ...........................................................................31 
3.4.6 Treatment Compliance ...............................................................................................31 
3.4.7 Rescue Medication .....................................................................................................31 
3.4.8 Prior and Concomitant Illnesses and Medications .....................................................32 
3.4.8.1 
Prior and Concomitant Illnesses ....................................................................................... 32 
3.4.8.2 
Prior and Concomitant Medications ................................................................................. 32 
3.4.8.3 
Prohibited Medications and Substances ............................................................................ 32 
3.4.9 Allowed Medications and Treatments .......................................................................33 
3.5 
Assessments .......................................................................................................................34 
3.5.1 Schedule of Assessments ...........................................................................................34 
3.5.2 Study Procedures .......................................................................................................39 
3.5.2.1 
Prescreening ...................................................................................................................... 39 
3.5.2.2 
Visit 1 – Screening Visit – (Day -21 to Day -1) ............................................................... 39 
3.5.2.3 
Visit 2 – T1 Baseline Visit – Day 0 .................................................................................. 40 
3.5.2.4 
Treatment 1 ....................................................................................................................... 40 
3.5.2.5 
Visit 8 (Treatment 1, Day 8 ± 2 days) .............................................................................. 42 
3.5.2.6 
Visit 9 (Treatment 1, Day 15 ± 2 days) ............................................................................ 42 
3.5.2.7 
Visit 10 (Treatment 1, Day 28 ± 2 days) .......................................................................... 43 
3.5.2.8 
Telephone Contact ............................................................................................................ 43 
3.5.2.9 
Visit 11 (Treatment 2 Baseline) ........................................................................................ 43 
3.5.2.10 
Treatment 2 .................................................................................................................... 44 
3.5.2.11 
Visit 17 (Treatment 2, Day 8 ± 2 days) .......................................................................... 46 
3.5.2.12 
Visit 18 (Treatment 2, Day 15 ± 2 days) ........................................................................ 46 
3.5.2.13 
Visit 19/End of Study/Early Termination (Treatment 2, Day 28 ± 2 days) ................... 46 
3.5.3 Assessments for Early Termination ...........................................................................47 
3.5.4 Pharmacodynamic Assessments ................................................................................47 
3.5.4.1 
Cortisol ............................................................................................................................. 47 
3.5.4.2 
Glucose ............................................................................................................................. 47 


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3.5.4.3 
White Blood Cell Count ................................................................................................... 48 
3.5.4.4 
Numeric Pain Rating Scale ............................................................................................... 48 
3.5.4.5 
Brief Pain Inventory - Short Form .................................................................................... 48 
3.5.5 Safety Assessments ....................................................................................................48 
3.5.5.1 
Physical Examination ....................................................................................................... 48 
3.5.5.2 
General Neurological and Targeted Neurological Examinations: .................................... 48 
3.5.5.3 
Vital Signs and Body Weight ........................................................................................... 49 
3.5.5.4 
Electrocardiogram ............................................................................................................. 49 
3.5.5.5 
Laboratory Parameters ...................................................................................................... 49 
3.5.5.6 
Adverse Events ................................................................................................................. 50 
3.5.6 Appropriateness of Measurements .............................................................................50 
4 
ADVERSE EVENT REPORTING........................................................................................51 
4.1 
Definitions and Criteria......................................................................................................51 
4.1.1 Adverse Events ..........................................................................................................51 
4.1.2 Serious Adverse Events .............................................................................................51 
4.1.3 Unexpected Adverse Drug Reactions ........................................................................52 
4.1.4 Abnormal Laboratory Values ....................................................................................52 
4.1.5 Assessing Intensity and Relationship.........................................................................52 
4.2 
Reporting Procedures and Requirements ...........................................................................53 
4.2.1 Adverse Events ..........................................................................................................53 
4.2.2 Adverse Events of Special Interest ............................................................................54 
4.2.3 Serious Adverse Events .............................................................................................54 
4.3 
Procedures for Documenting Pregnancy during the Study ................................................55 
5 
DATA MANAGEMENT AND STATISTICAL ANALYSIS ..............................................56 
5.1 
Data Management Considerations .....................................................................................56 
5.2 
Statistical Considerations ...................................................................................................56 
5.2.1 Sample Size Justification ...........................................................................................56 
5.2.2 Study Data ..................................................................................................................56 
5.2.3 Analysis Methods.......................................................................................................57 
5.2.4 Analysis Populations ..................................................................................................57 
5.2.5 Demographic and Baseline Characteristics ...............................................................58 
5.2.6 Pharmacodynamic Endpoints.....................................................................................58 


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5.2.7 Pharmacodynamic Analyses ......................................................................................58 
5.2.8 Safety Analyses ..........................................................................................................59 
5.2.8.1 
Adverse Events ................................................................................................................. 59 
5.2.8.2 
Laboratory Data ................................................................................................................ 59 
5.2.8.3 
Vital Signs......................................................................................................................... 59 
5.2.8.4 
Electrocardiographic Data ................................................................................................ 60 
5.2.8.5 
Physical Examination Findings ......................................................................................... 60 
5.2.9 Interim Analyses ........................................................................................................60 
6 
STUDY MANAGEMENT ....................................................................................................61 
6.1 
Ethics and Consent .............................................................................................................61 
6.1.1 Regulations and Guidelines .......................................................................................61 
6.1.2 Institutional Review Board/Independent Ethics Committees ....................................61 
6.1.3 Informed Consent.......................................................................................................61 
6.2 
Discontinuation of the Study by the Sponsor ....................................................................61 
6.3 
Study Documentation.........................................................................................................61 
6.4 
Study Monitoring and Auditing .........................................................................................61 
6.5 
Retention of Records ..........................................................................................................62 
6.6 
Use of Study Findings ........................................................................................................62 
6.7 
Publications ........................................................................................................................62 
7 
REFERENCES ......................................................................................................................63 
8 
APPENDICES .......................................................................................................................66 
Appendix A 
BMI Table ..............................................................................................................66 
Appendix B 
Cockcroft-Gault Equation ......................................................................................67 
Appendix C 
Morphine Equivalents ............................................................................................68 
Appendix D 
Instructions for Study Drug Injection ....................................................................69 
Appendix E 
Numeric Pain Rating Scale ....................................................................................71 
Appendix F 
Brief Pain Inventory-Short Form ...........................................................................73 
Appendix G 
Targeted Neurological Exam .................................................................................75 
Appendix H 
Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in 
Preventive Vaccine Clinical Trials. .......................................................................76 
 




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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Definition 
α 
alpha 
ACTH 
adrenocorticotropic hormone 
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) 
AUCinf 
area under the effect time curve from time zero extrapolated to 
infinity 
AUEC28 days 
area under the effect time curve at 28 days post dose 
BMI 
body mass index 
BP 
blood pressure 
BPI-SF 
Brief Pain Inventory-Short Form 
bpm 
beats per minute 
C 
Celsius 
CDISC 
Clinical Data Interchange Standards Consortium  
CI 
confidence interval 
Cmax 
maximum concentration 
CSF 
cerebrospinal fluid 
D 
day 
DDE 
direct data entry 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
Emax 
maximum effect 
EOS 
end of study 
ESI 
epidural steroid injection 
ET 
early termination 
F 
Fahrenheit 
FAERS 
FDA Adverse Event Reporting System 
FDA 
Food and Drug Administration 
FSH 
follicle stimulating hormone 
g 
gram 
GCP 
Good Clinical Practice 


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Abbreviation 
Definition 
HbA1c 
Hemoglobin A1c 
HIV 
human immunodeficiency virus 
HPA 
hypothalamic-pituitary-adrenal 
IB 
Investigator’s Brochure 
ICF 
informed consent form 
ICH 
International Council on Harmonisation of Technical Requirements 
for Pharmaceuticals for Human Use  
IL 
interlaminar(ly) 
IM 
intramuscular(ly) 
IND 
Investigational New Drug  
INR 
International Normalization Ratio 
IP 
investigational product 
IRB 
institutional review board 
IV 
intravenous(ly) 
LFT 
liver function tests 
µg 
microgram 
µmol 
micromole 
MEDD 
Mean Equivalent Daily Dose 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
milligram  
min 
minutes 
mITT 
Modified intent-to-treat (dataset) 
mIU 
milli international unit 
mL 
milliliter 
mm 
millimeter 
mmHg 
millimeters of mercury 
mRNA 
messenger ribonucleic acid 
MRI 
magnetic resonance imaging 
NPRS 
Numeric Pain Rating Scale 
NSAID 
nonsteroidal anti-inflammatory drug(s) 
OL 
open-label 
PD 
pharmacodynamic 
PT 
prothrombin time 
PTT 
partial prothrombin time 


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Abbreviation 
Definition 
RLD 
Reference Listed Drug 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SD 
standard deviation 
SDTM 
Study Data Tabulation Model 
SOP 
standard operating procedure 
T 
treatment 
TEAE 
treatment-emergent adverse event 
TF 
transforaminal(ly) 
Tmax 
time to maximum concentration 
US 
United States 
WBC 
white blood cells 
WOCBP 
women of childbearing potential 
 
 
 
 
 


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


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1 INTRODUCTION 
1.1 Background 
1.1.1 Lumbosacral Radicular Pain 
Back pain is a widespread, debilitating disorder that results in an enormous socioeconomic 
burden.  The lifetime prevalence of low back pain ranges from 60% to 90%, and the annual 
incidence is ~5% (Frymoyer-1988, Frymoyer-1992).  The annual cost to treat back pain has been 
estimated to exceed $100 billion, of which it is estimated that up to $50 billion is due to lost 
productivity (Cleeland-1989).   
A specific type of back pain in the distribution of lumbosacral nerves is known as lumbosacral 
radicular pain, which is frequently referred to as sciatica.  It is a common condition with a 
lifetime incidence varying from 13% to 40% (Stafford-2007).  The corresponding annual 
incidence of an episode of lumbosacral radicular pain ranges from 1% to 5% (Frymoyer-1988, 
Frymoyer-1992).  It is rarely diagnosed before the age of 20, peaks in incidence in the fifth 
decade of life and declines thereafter (Frymoyer-1992).   
Lumbosacral radicular pain is believed to result most commonly from prolapsed disc material 
causing pain secondary to mechanical impingement and/or inflammation of the anterior primary 
rami of lumbar nerve roots.  Histological changes have been first described in 1951 
(Lindahl-1951).  Approximately 90% of cases of lumbosacral radicular pain are caused by a 
herniated disc with nerve root compression, with various other etiologies accounting for the 
remaining 10% of the cases (Stafford-2007, Valat-2010).  
There are several conservative treatments for lumbosacral radicular pain, each with varying 
levels of effectiveness.  These therapeutic approaches include bed rest, staying active (in contrast 
to bed rest), analgesic or non-steroidal anti-inflammatory drugs (NSAIDs), acupuncture, spinal 
manipulations, traction therapy, physical therapy, behavioral treatment, and epidural steroid 
injections (ESIs) (Frymoyer-1992, Koes-2007, Valat-2010).  The initial phase of sciatica 
frequently responds to conservative management with no intervention.  For example, in a study 
of more than 208 subjects with obvious symptoms and signs of a lumbosacral radicular pain 
(5th lumbar vertebra and 1st sacral vertebra), treated with nonsteroidal anti-inflammatory drug 
piroxicam or placebo, 70% in active group reported a marked reduction in back and leg pain and 
improved functionality within 4 weeks and 60% had returned to work at that point in time.  
However, approximately 30% of subjects in both groups still complained of back pain and 19.5% 
were out of work after 1 year (Weber-1993).  When these more conservative treatments for 
lumbosacral radicular pain are ineffective, ESIs or surgical interventions are commonly used. 
Epidural cocaine injections were reported as early as 1901 via the sacral hiatus for lumbosacral 
radicular pain (Nelson-2001).  In the 1950s, physicians began injecting corticosteroids into the 
epidural and extradural space as a treatment for lumbosacral radicular pain (Barry-1962, 
Benzon-2015).  
1.1.2 Epidural Steroids 
The first controlled trial evaluating ESIs was performed in 1970 (Sullivan-1995) and since then 
there have been many controlled trials evaluating the effectiveness of different corticosteroids 
injected into the epidural space for the treatment of radicular pain.  Despite differences in 
injection route, anatomical region of injection, control group, injectate characteristics, and 


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individual pathology, the clinical consensus across multiple practice specialties is that ESIs 
provides at least short-term benefit in selected people (Cohen-2013).   
The mechanisms by which steroids exert their analgesic effects have been debated, but it is 
established that corticosteroids inhibit phospholipase A2, which catalytically hydrolyzes the 
bond converting membrane phospholipids into arachidonic acid and lysophospholipids 
(Cohen-2013).  In addition to the anti-inflammatory effects, steroids may also inhibit pain via 
their ability to suppress ectopic discharges from injured nerve fibers and depress conduction in 
normal unmyelinated C fibers (Devor-1985, Johansson-1990).  Epidural steroids are now 
considered a standard treatment regimen for lumbosacral radicular pain (Cohen-2013).  The 
comparative effectiveness of the various treatment modalities has been a topic that has been 
frequently addressed in the literature, but there is currently no United States (US) Food and Drug 
Administration (FDA)-approved epidural steroid treatment for lumbosacral radicular pain. 
Epidural injection of corticosteroids is a common procedure performed in the US for the 
management of lumbar radicular pain caused by disc herniations.  They have been shown 
effective in reducing pain, restoring function, reducing the need for other health care, and 
avoiding surgery (MacVicar-2013).  Recent review of randomized controlled clinical trials using 
ESIs for treatment of radicular pain demonstrate Level II clinical evidence of long-term benefits 
(Kaye-2015).  ESIs are relatively safe procedures, containing lower risks than opioid therapy 
(Cohen-2013).  
Because injectable corticosteroids are not FDA‐approved for this route of administration, the 
epidural injection of corticosteroids is considered an off‐label use of approved injectable steroid 
formulations.   
In 2009, the FDA began evaluating serious neurologic events associated with epidural 
glucocorticoid injections.  Between 1997 and 2014, a total of 90 serious and sometimes fatal 
neurologic events were reported to the FDA Adverse Event Reporting System (FAERS), 
including cases of paraplegia, quadriplegia, spinal cord infarction, and stroke.  There is concern 
that in glucocorticoids formulated as suspensions rather than solutions, particulate matter may 
pose an increased risk of embolism after inadvertent intravascular injection.  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 (Racoosin-2015).  In 2014, the FDA issued a requirement 
that all injectable glucocorticoid product labels carry a warning stating that “serious neurologic 
events, some resulting in death, have been reported with epidural injection of corticosteroids” 
and that the “safety and effectiveness of epidural administration of corticosteroids have not been 
established and corticosteroids are not approved for this use” (Food and Drug 
Administration-2014). 
The Anesthetic and Analgesic Drug Products Advisory Committee held a meeting on 
November 24‐25, 2014 to discuss the risk of serious neurologic adverse reactions associated with 
ESIs administered to reduce inflammation for pain management.  The Committee considered the 
efficacy of ESI and the overall risk‐benefit balance of injecting steroids in the epidural space to 
treat pain.  The committee acknowledged the benefits of ESIs.  The safety concerns are related to 
particulate-containing formulations leading to 131 neurological adverse events (AEs), including 
41 cases of arachnoiditis, identified by the FDA, and 700 cases of fungal meningitis following 










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2 STUDY OBJECTIVES 
2.1 
Primary Objective 
The primary objective of the study is to characterize repeat dose PD of SP-102 (10 mg 
dexamethasone) administered by epidural injection with respect to HPA suppression using 
plasma cortisol levels, WBC count, and blood glucose. 
2.2 Secondary Objectives 
The secondary objectives of the study are to:  
• Evaluate the safety and tolerability of single and repeat dose SP-102 (10 mg 
dexamethasone) administered by epidural injection in subjects with lumbosacral 
radiculopathy. 
• Evaluate the analgesic effect on leg pain (as measured by the Numeric Pain Rating Scale 
[NPRS] in the affected leg) following the index (Treatment [T] 1) and repeat (T2) 
injections. 
  
 


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3 INVESTIGATIONAL PLAN 
3.1 Overall Study Design and Plan  
This is an open-label, single-arm, repeat dose study to characterize the PD and safety/tolerability 
of SP-102 (10 mg dexamethasone) administered by TF or IL injection under fluoroscopic 
guidance in subjects with lumbosacral radiculopathy.  
Subjects meeting the eligibility criteria will be enrolled in the study and receive a single 2-mL 
epidural injection of SP-102 (10 mg dexamethasone) in T1 (index injection) and T2 (repeat 
injection), separated by 4 to 8 weeks.  T2 will only be provided if a repeat injection is warranted 
and the subject continues to meet applicable study inclusion and exclusion criteria. 
Subjects who have been using opioids other than high dose opioids within 30 days prior to 
Screening (see Exclusion #12), may participate in the study if they agree to discontinue the 
opioid therapy prior to the Screening Visit and sign the pre-screening informed consent form 
(ICF). 
The study will include a 21-day screening period (Visit 1), sequential treatments periods T1 and 
T2, separated by 4 to 8 weeks; each treatment period will consist of a Baseline Visit (Day 0), 
SP-102 injection (Day 1), and a 4-week follow-up period.  Screening, Baseline, and follow-up 
visits will occur at the research site.  Subjects will stay in a restricted environment (
) for 
each of 5 nights beginning the night before each injection to ensure fasting each evening and on-
time collection of PD assessments each morning.  Subjects will be permitted to leave the 
restricted environment 
) and resume normal activities each day after study procedures 
are performed.  The SP-102 injection will be administered in an injection procedure facility.  
Safety and PD assessments will be collected at Screening, pre-dose, daily for 4 days post dose 
during the stay in the restricted environment (
), and at 3 outpatient follow-up visits (on 
Day 8, Day 15, and Day 28) after each injection.  The end of study (EOS) visit (Visit 19) is the 
final outpatient visit after the second injection.  If the subject is not eligible for T2 or chooses to 
withdraw from further participation in the study, the subject will be scheduled for the EOS visit 
(Visit 19). 






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disease) at the Screening or Baseline Visit that would preclude the use of dexamethasone 
in this study.   
4. Has a major psychiatric disorder not controlled with medication at the Screening or 
Baseline Visit that would interfere with clinical pain scores or participation in the trial. 
5. History of any disorder related to cortisol production (eg, hyper- or hypo-cortisolism, 
Cushing’s syndrome, pituitary tumor, Addison’s disease, Nelson syndrome) at the 
Screening or Baseline Visit.   
6. History of malignancy or evidence of malignancy or lymphoproliferative or neoplastic 
disease with the exception of successfully treated basal or squamous cell carcinoma of 
the skin or cervical intraepithelial neoplasia within 5 years of the Screening Visit.   
7. History of allergy to corticosteroids or anaphylactoid reaction to any other drug at the 
Screening or Baseline Visit. 
8. Known allergy or idiosyncratic (atopic) reaction to contrast agent, local anesthetic, 
dexamethasone, any ingredient listed as being present in a study formulation, or any other 
pain management compound likely to be prescribed in the study. 
9. Abnormalities in clinical chemistry that would place the subject at undue risk after 
epidural steroid injection, per the discretion of the principal investigator.  These 
abnormalities include but are not limited to:  
a. serum glutamic-oxaloacetic transaminase/aspartate aminotransferase (AST) or serum 
glutamic-pyruvic transaminase/alanine aminotransferase (ALT) ≥ 3 times the upper 
limit of the reference range at the Screening Visit   
b. Coagulation abnormalities: INR > 1.5 or platelet count < 100,000/mm3) 
c. HIV, Hepatitis B, or Hepatitis C virus infection 
10. Creatinine clearance < 60 mL/min as estimated by Cockcroft-Gault equation (Appendix 
B) at the Screening Visit. 
11. Chronic use (ie, more than 5 consecutive days) of oral or parenteral steroid medication 
during the 2 months prior to the Screening Visit and any oral or parenteral steroid 
medication in the 2 weeks prior to the Screening Visit or to the Baseline Visit. 
12. Regular use of high dose opioids (> 30 mg morphine equivalents for more than 2 days 
per week) in the 30 days prior to the Screening Visit (Appendix C).  The subject must 
agree to discontinue all opioids prior to the Screening Visit. 
13. An epidural steroid injection for the treatment of the current episode of lumbosacral 
radicular pain during the 2 months prior to the Screening Visit.   
14. History of spine surgery prior to the Screening or Baseline Visit, which may interfere 
with IL epidural injection, or plans to undergo spine surgical intervention while in the 
study.   
15. Has donated blood exceeding 500 mL during the 45 days before Baseline Visit. 
16. Use of any investigational drug or device within 30 days prior to the Screening Visit or is 
scheduled to receive an investigational drug other than study drug during the course of 
this study.   


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17. If female, are lactating/breastfeeding, plan to breastfeed, currently pregnant, or plan to 
become pregnant while participating in the study. 
18. Alcohol dependence, drug abuse, or drug addiction within 1 year of the Screening Visit. 
19. 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. 
20. The presence of any disorder, condition, laboratory abnormality, or circumstance (with 
the exception of the condition under study) as determined by a medical and psychiatric 
history, medical examination, electrocardiogram (ECG), serum chemistry, hematology, 
and urinalysis that, in the opinion of the investigator, has the potential to compromise 
subject safety, prevent study completion, and/or to have a confounding effect on outcome 
measures. 
3.3.3 Stopping Rules 
A single occurrence of an adverse event of special interest (AESI) (Section 4.2.2) precludes the 
subject from 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 
Visit 19 (End of Study [EOS]/Early Termination [ET]) 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 EOS/ET assessments as shown in Section 3.5.1.  Enrollment will 
continue until 12 subjects have each completed two SP-102 injections (T1 and T2).   
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 SAEs, nonserious AEs, and AESIs 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. 












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3.5.3 Assessments for Early Termination 
If the subject’s participation in the study is terminated prematurely for any reason, the reason for 
such ET should be documented and the Visit 19/EOS/ET procedures should be performed.  If the 
ET occurs prior to Visit 10, the subject should be encouraged to continue in the study until 
Visit 10, if possible.  Subjects who do not receive both T1 and T2 will be discontinued from the 
study and the Visit 19/EOS/ET procedures should be performed.  In case of ET, the subject 
should be encouraged to return to the site for ET procedures, or failing a return visit, a telephone 
visit should be arranged to encourage the subject to complete the Visit 19/EOS/ET procedures 
(Section 3.5.2.13). 
An EOS eCRF page should be completed for every subject who receives IP, whether the subject 
completes the study or not.  The reason for any ET should be indicated on this form.  The primary 
reason for the ET should be selected as noted in Section 3.3.4. 
3.5.4 Pharmacodynamic Assessments 
3.5.4.1 Cortisol 
Blood is collected to measure the level of the hormone cortisol in the blood, which may indicate 
problems with the adrenal glands or pituitary gland.  Ideally, this test should be performed at 
8 am after at least a 10-hour fast; this is not required at Screening.  Cortisol will be measured 
from blood samples collected at Screening, Visit 3 through Visit 10, and Visit 12 through 
Visit 19.  NOTE: The Screening test result is to be compared to the local laboratory normal range 
for cortisol daily variation. 
3.5.4.2 Glucose 
A glucose level measures the amount of sugar circulating in the blood.  Accurate levels of 
glucose are measured from blood obtained in a fasting state; therefore, the subject will undergo 
at least a 10-hour fast prior to this being tested at 8 am; this is not required at Screening.  
Glucose will be measured at Screening, Visit 3 through Visit 10, and Visit 12 through Visit 19.  
NOTE: The Screening test result is to be compared to the local laboratory normal range for 
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3.5.4.3 White Blood Cell Count 
The WBC count tabulated the number of WBC circulating in the blood.  WBC will be measured 
at Screening, Visit 3 through Visit 10, and Visit 12 through Visit 19. 
3.5.4.4 Numeric Pain Rating Scale  
The NPRS (Appendix E) is an 11-point scale (0 to 10-point scale where 0 is no pain and 10 is 
worst pain imaginable) that allows the subject to rate the severity of their pain intensity at 
various points in time (Turk-2003).  The subject will use the NPRS to record their current pain, 
average pain in the past 24 hours, and worst pain in the past 24 hours for both their affected 
leg(s) and back pain.  The NPRS will be collected at each study visit.  
3.5.4.5 Brief Pain Inventory - Short Form 
The BPI-SF (Appendix F) 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 all study visits except Screening. 
3.5.5 Safety Assessments 
3.5.5.1 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.  The Screening physical examination will also include an 
assessment of lumbosacral radiculopathy.  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.  A 
physical examination will be done at Screening, T1 – Day 0, T1 – Day 28, and T2 – Day 28 
(Visit 19/EOS/ET).  
3.5.5.2 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 focusing on signs and symptoms of 
lumbosacral radiculopathy, including straight leg raise test, will be performed according to the 
checklist (see Appendix G).  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 pre-dose and post dose on T1 – Day 1, pre-dose and post dose on T2 – Day 1, and on 
T2 – Day 28 (Visit 19/EOS/ET).  


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3.5.5.3 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 min 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.  Vital signs will be recorded at each clinic visit and will be monitored 
within 15 min prior to the procedure, approximately every 5 min during the procedure (prior to 
syringe removal), and approximately every 15 min after for 60 min after the procedure.  Height 
(in inches without shoes) and weight (in pounds) will be recorded at Screening.  Weight will also 
be recorded at T1 – Day 0, T1 – Day 28, and T2 – Day 28 (Visit 19/EOS/ET). 
3.5.5.4 Electrocardiogram  
Standard 12-lead ECGs will be measured in triplicate on the site machines after the subject has 
been supine for at least 5 min at Screening, Baseline, T1 – Day 28, and T2 – Day 28 
(Visit 19/EOS/ET).  The ECG results will be documented in the eCRF. 
3.5.5.5 Laboratory Parameters  
The following clinical laboratory tests are to be performed at Screening, Baseline, T1 – Day 5, 
T1 – Day 28, T2 – Day 5, and T2 – Day 28 (Visit 19/EOS/ET) unless noted below:  
Hematology: Hemoglobin, hematocrit, red blood cell count, WBC count (with 
differential [lymphocytes, neutrophils, eosinophils, basophils, and monocytes]), and 
platelet count.   
Serum Chemistry: albumin, alkaline phosphatase, AST, ALT, direct bilirubin, total 
bilirubin, blood urea nitrogen, calcium, chloride, creatine kinase (Screening only), 
creatinine, gamma-glutamyl transferase, glucose, lactate dehydrogenase, potassium, 
sodium, and uric acid. 
Other tests: HbA1c, HIV, hepatitis B, and hepatitis C at Screening.  Coagulation tests at 
Screening or Baseline: activated PTT, PT, and INR.  Coagulation tests may be repeated 
prior to the index and repeat injection, if deemed necessary by the Investigator. 
Urinalysis: Dipstick analysis: color, turbidity, specific gravity, pH, glucose, protein, 
ketones, urobilinogen, bilirubin, blood nitrate, leukocyte esterase, and microscopic 
examination when indicated by dipstick results. 
Urine drug screen: Includes opiates, barbiturates, benzodiazepines, tricyclic 
antidepressants, cannabinoids, PCP, cocaine, ecstasy, and amphetamines.  A urine drug 
screen will be obtained at Screening, Baseline, and T1 – Day 28.  A urine drug screen 
may be repeated if deemed necessary by the Investigator.   
WOCBP: Serum pregnancy test at Screening.  Urine pregnancy test at Baseline and at 
Visit 11 (T2 – Day 0).  A urine pregnancy test may be repeated if deemed necessary by 
the Investigator.  
Laboratory samples will be analyzed by the local laboratory.  In the event of an unexplained 
clinically noteworthy abnormal laboratory test value, the test should be repeated immediately 
and followed up until it has returned to the normal range and/or an adequate explanation of the 
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3.5.5.6 Adverse Events  
All AEs occurring after the subject signs the ICF through EOS/ET (Visit 19) will be recorded.   
See Section 4 for additional information. 
3.5.6 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-1994).  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 
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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-2017).  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 H) 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 H. 
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 
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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 Semnur confirming that the subject is lost to follow-up.  SAEs that 
are ongoing at EOS 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. 
If the investigator detects an SAE in a study subject within 30 days after the last scheduled study 
visit, and considers the SAE related or possibly related to prior study treatment, the investigator 
should report it to sponsor/
 
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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5.2.3 Analysis Methods 
No formal statistical hypothesis testing will be performed in this study, however descriptive 
statistics will be presented. 
Unless otherwise specified, baseline is defined as the last non-missing measurement taken prior 
to treatments T1 or T2 (reference start date).  This includes screening or unscheduled 
assessments that would have been performed no earlier than 21 days before the reference start 
date. 
In the case where the last non-missing measurement and the reference start date coincide, that 
measurement will be considered pre-reference, but AEs and medications commencing on the 
reference start date will be considered post-reference. 
For vital signs parameters, an assessment performed on reference start date with time point 
marked as “pre-dose” will be considered as baseline.  
For cortisol suppression, glucose, and white blood cell counts, baseline is defined as the last 
non-missing value obtained prior to T1 or T2, which is T1/T2 Day 1 pre-dose measurement. 
For NPRS, baseline is defined as the last non-missing value obtained prior to T1 or T2, which is 
T1/T2 Day 0 measurement. 
Details on definition of baseline and calculations for the change and percent change in PD values 
will be defined in detail in the SAP. 
5.2.4 Analysis Populations 
The Safety Analysis population is defined as all enrolled subjects who receive at least one 
SP-102 injection.   
The PD Analysis population is defined as all enrolled subjects who have a T1 period baseline PD 
result and at least 1 postdose PD assessment result without any protocol deviations available in 
either T1 or T2.   
The Complete Analysis population is defined as all enrolled subjects who receive only one 
SP-102 injection who complete T1 – Day 28 plus those subjects who receive two SP-102 
injections who complete T2 – Day 28.  
Protocol deviations should be collected by site and grouped into different categories, such as 
those who: 
• Entered the study even though they did not satisfy the entry criteria; 
• Developed withdrawal criteria during the study but were not withdrawn; 
• Received the incorrect dose; 
• Received an excluded concomitant treatment. 
Major protocol violations that impact the PD analysis may lead to exclusion from the PD 
population.  Full details regarding these will be provided in the SAP. 


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5.2.5 Demographic and Baseline Characteristics 
Treatment groups will be compared with respect to subject demographics and baseline 
characteristics and will be summarized using descriptive statistics, but no formal statistical 
analysis testing will be performed. 
5.2.6 Pharmacodynamic Endpoints  
• Dexamethasone-induced HPA suppression as measured by: 
o Observed total blood cortisol levels, change from baseline cortisol levels, and 
percent change from baseline cortisol levels 
o Observed glucose levels, change from baseline glucose levels, and percent change 
from baseline glucose levels 
o  Observed white blood cell counts, change from baseline white blood cell counts, 
and percent change from baseline white blood cell counts 
• NPRS (average leg pain and back pain) and BPI-SF  
• Change from T1 Day 0 and T2 Day 0 through Day 28 in NPRS (average leg pain and 
back pain) and BPI-SF over time following the index (T1) and repeat (T2) epidural 
injections, respectively  
• Percent change from T1 Day 0 and T2 Day 0 through Day 28 in NPRS (average leg pain 
and back pain) and BPI-SF following the index (T1) and repeat (T2) epidural injections, 
respectively 
5.2.7 Pharmacodynamic Analyses 
All PD analyses will use the PD population as the primary analysis population.   
Cortisol levels, WBC counts, and fasting blood glucose levels (observed, change from baseline, 
and percent change from baseline) will be summarized by treatment and measurement time using 
descriptive statistics.  Dexamethasone-induced HPA suppression will be evaluated by using the 
observed total plasma cortisol level, blood glucose levels, and WBC count.  Other PD analyses 
may be performed as appropriate.  For these PD endpoints, the pre-dose morning values will be 
determined for each subject as a Baseline for each treatment and the data will be presented as 
observed value, change from baseline, and as a percent of Baseline value.   
The following pain-score endpoints will be summarized over time by treatment using descriptive 
statistics: 
• NPRS (average leg pain and back pain) and BPI-SF  
• Change from T1 Day 0 and T2 Day 0 through Day 28 in NPRS (average leg pain and 
back pain) and BPI-SF over time following the index (T1) and repeat (T2) epidural 
injections, respectively  
• Percent change from T1 Day 0 and T2 Day 0 through Day 28 in NPRS (average leg pain 
and back pain) and BPI-SF following the index (T1) and repeat (T2) epidural injections, 
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For blood cortisol and glucose levels, and WBC counts (change‐from‐baseline), PD parameters, 
ie, area under the effect curve over 28 days (AUEC28 days) and maximum effect (Emax) following 
the T1 (index) and T2 (repeat) injections will be calculated.   
AUEC28 days is defined as the change from baseline (for cortisol, glucose, and WBC) and 
calculated using linear trapezoidal summation from pre-dose to Day 28 in each treatment period.  
Emax is the baseline-adjusted maximum increase in glucose level and WBC count or the 
maximum decrease in cortisol levels over the 28 days post dose in each treatment period.  
The PD parameters will be analyzed using a mixed model analysis of variance using 
PROC MIXED with a fixed effect for treatment and a random effect for subject.  Estimates and 
90% confidence intervals (CIs) will be first constructed in the logarithmic scale.  By taking 
anti-logarithms, estimates and CIs for the geometric means and ratios of geometric means will be 
calculated.  All CIs will be 2-sided.  
A lack of effect of repeat injection on the PD will be concluded if the 90% CIs for the ratio of T2 
(repeat injection; Test) to T1 (index; Reference) for both AUEC28 days and Emax are completely 
contained within the range of 80 to125%. 
5.2.8 Safety Analyses 
Safety endpoints are as follows: 
• Incidence of treatment-emergent adverse events (TEAEs) and SAEs 
• Change from baseline in clinical laboratory parameters, vital sign measurements, ECG 
findings, physical examination, general neurological examination findings, and targeted 
neurological examination findings following each treatment 
5.2.8.1 Adverse Events 
All AEs will be coded using the most current version of MedDRA.  TEAEs and SAEs will be 
summarized descriptively for each treatment.   
5.2.8.2 Laboratory Data 
Mean changes from Baseline 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. 
5.2.8.3 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) 


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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 
5.2.8.4 Electrocardiographic Data 
A listing of 12-lead ECG parameter results will be presented.  Shifts in ECG parameters will be 
summarized by treatment group from Screening to each post dose visit at which ECG 
assessments are obtained. 
5.2.8.5 Physical Examination Findings 
Shifts in physical examination findings will be summarized by treatment group from Screening 
to each post dose visit at which a physical examination was performed. 
5.2.9 Interim Analyses 
No interim analysis is planned for this study.   
 


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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) 
(ICH-E6-1996), 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 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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will include a review of forms for completeness and clarity, and consistency with electronic or 
paper source documents (if used) for each subject.   
Medical advisors and CRAs or assistants may request to witness subject evaluations occurring as 
part of this protocol.  The investigator and appropriate personnel will be periodically requested to 
attend meetings/workshops organized by the sponsor to assure acceptable protocol execution.  
The study may be subject to audit by the sponsor or by regulatory authorities.  If such an audit 
occurs, the investigator must agree to allow access to required subject records.  By signing this 
protocol, the investigator grants permission to personnel from the sponsor, its representatives, 
and appropriate regulatory authorities, for on-site monitoring of all appropriate study 
documentation, as well as on-site review of the procedures employed in eCRF generation, where 
clinically appropriate. 
6.5 
Retention of Records 
The investigator must arrange for retention of study records at the site for 2 years after the IP’s 
New Drug Application is approved or the IND is withdrawn, as required by FDA regulations.  
The investigator should take measures to prevent accidental or premature destruction of these 
documents. 
6.6 
Use of Study Findings 
By signing the study protocol, the investigator agrees to the use of results of the study for the 
purposes of national and international registration.  If necessary, the authorities will be notified 
of the investigator’s name, address, qualifications, and extent of involvement.  Reports covering 
clinical and biometric aspects of the study will be prepared by the sponsor or its representative. 
6.7 
Publications 
As a multicenter trial, the sponsor intends to publish clinical data from all centers participating in 
the investigation.  A publication committee selected by the sponsor will submit draft manuscripts 
to all participating investigators for their comments.  In conformity with the Uniform 
Requirements for Manuscripts Submitted to Biomedical Journals published by the International 
Committee of Medical Journal Editors, investigators whose contribution consists solely in the 
collection of data will not be named individually as authors (Kassirer-1991).  Rather, those 
investigators will receive a collective authorship and will be identified in a note. 
Individual investigators and/or their associates subsequently may publish additional findings of 
this study in scientific journals or present them at scientific meetings, if the sponsor is given 
ample opportunity to review any proposed abstract, manuscript, or slide presentation before its 
submission.  This review is required to ensure that the sponsor is aware of all written and oral 
presentations of the data and does not imply any editorial review or restriction of the contents of 
the presentation or use. 
 
 


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7 REFERENCES 
1. Horlocker TT, Wedel DJ, Rowlingson JC, Enneking FK, Kopp, SL, Benzon HT, Brown DL, 
Heit, JA, Mulroy MF, Rosenquist RW, Tryba M, Yuan, C.  ASRA Practice Advisory: 
Anticoagulation 3rd Edition: Regional Anesthesia and Pain Medicine. January/February 2010 
- Volume 35 - Issue 1 - pp 64-101.  doi: 10.1097/AAP.0b013e3181c15c70. 
2. Barry PJ, Kendall PH.  Corticosteroid Infiltration of the Extradural Space.  Ann Phys Med.  
1962;6:267-273. 
3. Benzon HT, Huntoon MA, Rathmell JP.  Improving the Safety of Epidural Steroid Injections. 
JAMA 2015 May 5;313(17):1713-4.  
4. Canale L.  [Epidural Sacral Administration of Dexamethasone in Lumbar Sciatica].  Gazz 
Med Ital.  1963;122:210-213. 
5. Cohen SP, Bicket MC, Jamison D, et al.  Epidural Steroids: A Comprehensive, 
Evidence-Based Review.  Reg Anesth Pain Med.  2013;38(3):175-200. 
6. Cleeland CS.  Measurement of pain by subjective report.  In: Chapman CR, Loeser JD (Eds.).  
Advances in Pain Research and Therapy, Volume 12: Issues in Pain Measurement.  Raven 
Press, New York; 1989:391-403. 
7. Devor M, Govrin-Lippmann R, Raber P.  Corticosteroids Suppress Ectopic Neural Discharge 
Originating in Experimental Neuromas.  Pain.  1985;22(2):127-137. 
8. Dawley JD, Moeller-Bertram T, Wallace MS, Patel PM., Intra-arterial injection in the rat 
brain: evaluation of steroids used for transforaminal epidurals.  Spine (Phila Pa 1976).  2009 
Jul 15;34(16):1638-43.  doi: 10.1097/BRS.0b013e3181ac0018. PMID: 19770605.  
9. El-Yahchouchi C, Geske JR, Carter RE, et al.  The Noninferiority of the Nonparticulate 
Steroid Dexamethasone vs the Particulate Steroids Betamethasone and Triamcinolone in 
Lumbar Transforaminal Epidural Steroid Injections.  Pain Med.  2013;14(11):1650-1657. 
10. Food and Drug Administration.  Guidance for Industry Electronic Source Data in Clinical 
Investigations.  September 2013.  
11. Food and Drug Administration.  FDA Drug Safety Communication: FDA Requires Label 
Changes to Warn of Rare but Serious Neurologic Problems after Epidural Corticosteroid 
Injections for Pain.  April 23, 2014 (http://www.fda.gov/Drugs/DrugSafety/ucm394280.htm). 
12. Frymoyer JW.  Back Pain and Sciatica.  N Engl J Med.  1988;318(5):291-300. 
13. Frymoyer JW.  Lumbar Disk Disease: Epidemiology.  Instr Course Lect.  1992;41:217-223. 
14. Grady JA, 2008: Thesis, Pharmacokinetics and Pharmacodynamics of Oral Dexamethasone 
in Healthy Horses.  Kansas State University. 
15. International Conference on Harmonisation.  Guideline for Good Clinical Practice, ICH E6.  
June 10, 1996. 
16. International Conference on Harmonisation.  ICH Harmonised Tripartite Guideline Clinical 
Safety Data Management: Definitions and Standards for Expedited Reporting E2A.  October 
27, 1994. 
17. Iverson C, et al.  American Medical Association Manual of Style, 10th Edition.  New York, 
NY: Oxford University Press, Inc.; 2007. 


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18. Johansson A, Hao J, Sjolund B.  Local corticosteroid application blocks transmission in 
normal nociceptive C-fibres.  Acta Anaesthesiol Scand.  1990;34(5):335-338. 
19. Kassirer JP, Angell M.  On Authorship and Acknowledgments.  N Engl J Med 1991;325(21): 
510-12.  
20. Kaufmann TJ, Geske JR, Murthy NS, et al.  Clinical Effectiveness of Single Lumbar 
Transforaminal Epidural Steroid Injections.  Pain Med.  2013;14(8):1126-1133. 
21. Kaye AD, Manchikanti L, Abdi S, Atluri S, Bakshi S, Benyamin R, Boswell MV, 
Buenaventura R, Candido KD, Cordner HJ, Datta S, Doulatram G, Gharibo CG, Grami V, 
Gupta S, Jha S, Kaplan ED, Malla Y, Mann DP, Nampiaparampil DE, Racz G, Raj P, Rana 
MV, Sharma ML, Singh V, Soin A, Staats PS, Vallejo R, Wargo BW, Hirsch JA Efficacy of 
Epidural Injections in Managing Chronic Spinal Pain: A Best Evidence Synthesis.  Pain 
Physician 2015; 18:E939-E1004 • ISSN 2150-1149 
22. Kennedy DJ, Plastaras C, Casey E, et al.  Comparative Effectiveness of Lumbar 
Transforaminal Epidural Steroid Injections with Particulate Versus Nonparticulate 
Corticosteroids for Lumbar Radicular Pain due to Intervertebral Disc Herniation: A 
Prospective, Randomized, Double-Blind Trial.  Pain Med.  2014;15(4):548-555. 
23. Koes BW, van Tulder MW, Peul WC.  Diagnosis and Treatment of Sciatica.  BMJ.  
2007;334(7607):1313-1317. 
24. Lindahl O, Rexed B.  Histologic Changes in Spinal Nerve Roots of Operated Cases of 
Sciatica.  Acta Orthop Scand.  1951;20(3):215-225. 
25. Ma V, Shakir A.  The Impact of Type 2 Diabetes on Numeric Pain Score Reduction 
Following Cervical Transforaminal Epidural Steroid Injections.  Skeletal Radiol.  
2013;42(11):1543-1547. 
26. MacVicar J, King W, Landers MH, Bogduk N.  The Effectiveness of Lumbar Transforaminal 
Injection of Steroids: A Comprehensive Review with Systematic Analysis of The Published 
Data.  Pain Med.  2013;14(1):14-28. 
27. Manchikanti L, Benyamin RM.  Key Safety Considerations when Administering Epidural 
Steroid Injections.  Pain Manag.  2015;5(4):261-272. 
28. Nelson DA, Landau WM.  Intraspinal Steroids: History, Efficacy, Accidentality, And 
Controversy with Review of United States Food and Drug Administration Reports.  J Neurol 
Neurosurg Psychiatry.  2001;70(4):433-443. 
29. Pereira J, Lawlor P, Vigano A, Dorgan M, Bruera E. Equianalgesic Dose Ratios for Opioids. 
A Critical Review and Proposals for Long-Term Dosing. J Pain Symptom Manage. 
2001;22(2):672-687. 
30. Racoosin JA, Seymour SM, Cascio L, Gill R.  Serious Neurologic Events after Epidural 
Glucocorticoid Injection-The FDA's Risk Assessment.  N Engl J Med.  2015 Dec 
10;373(24):2299-301.  doi: 10.1056/NEJMp1511754.  Epub 2015 Oct 7.   
31. Rathmell JP, Benzon HT, Dreyfuss P, et al.  Safeguards to Prevent Neurologic Complications 
after Epidural Steroid Injections: Consensus Opinions from A Multidisciplinary Working 
Group and National Organizations.  Anesthesiology 2015;122:974-84. 


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32. Semnur Pharmaceuticals.  SP-102 (10mg dexamethasone) Investigator Brochure.  2nd ed.  
2017. 
33. Stafford MA, Peng P, Hill DA.  Sciatica: A Review of History, Epidemiology, Pathogenesis, 
and the Role of Epidural Steroid Injection in Management.  Br J Anaesth.  
2007;99(4):461-473. 
34. Sullivan MJL, Bishop SR, Pivik J.  The Pain Catastrophizing Scale: Development and 
Validation.  Psychological Assessment 1995; 7: 524-532. 
35. Troshin VD, Iskanderova AA.  Treatment of Lumbosacral Radiculitis with Epidural 
Dexamethasone Administration.  Zh Nevropatol Psikhiatr Im S Korsakova.  
1970;70(7):1010-1013. 
36. Turk DC, Dworkin RH, Allen RR, et al.  Core Outcome Domains for Chronic Pain Clinical 
Trials: IMMPACT Recommendations.  Pain.  2003;106(3):337-345. 
37. Valat JP, Genevay S, Marty M, Rozenberg S, Koes B.  Sciatica.  Best Pract Res Clin 
Rheumatol.  2010;24(2):241-252. 
38. Weber H, Holme I, Amlie E.  The Natural Course of Acute Sciatica with Nerve Root 
Symptoms in a Double-Blind Placebo-Controlled Trial Evaluating the Effect of Piroxicam.  
Spine (Phila Pa 1976).  1993;18(11):1433-1438. 
 


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8 APPENDICES 
Appendix A BMI Table 
 
 
 
 
 
 
 
 
 
 
 
 
 




















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Appendix H Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers 
Enrolled in Preventive Vaccine Clinical Trials. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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SAP_001.pdf: 
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SP-102-03 
Statistical Analysis Plan 
Version 1.0 
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Effective Date: 15-Apr-2016 
 
Confidential 
 
 
 
 
Statistical Analysis Plan 
Title: An Open-label, Single-arm Study to Characterize the Pharmacodynamics 
and Safety of Repeat Dose SP-102 (Dexamethasone Sodium Phosphate Injectable 
Gel) Administered by Epidural Injection in Subjects with Lumbosacral 
Radiculopathy 
 
Protocol Number: SP-102-03 
 
Version 1.0 
Issue Date: 05-FEB-2019 
Author: 
 
 
Previous Versions 
 
 
 


 
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SAP Amendments before database lock 
 
Version  Issue Date 
Section 
Revision/Addition 
Rationale 
 
 
 
 
 
 
 


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Table of Contents 
1 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ..................... 5 
2 
INTRODUCTION ............................................................................................... 6 
3 
STUDY OBJECTIVES ....................................................................................... 6 
3.1 
Primary Objective ........................................................................................................... 6 
3.2 
Secondary Objective ....................................................................................................... 6 
4 
ENDPOINTS ....................................................................................................... 7 
4.1 
Pharmacodynamic Endpoints .......................................................................................... 7 
4.2 
Safety Endpoints ............................................................................................................. 7 
5 
SAMPLE SIZE .................................................................................................... 7 
6 
RANDOMIZATION ........................................................................................... 7 
7 
PLANNED ANALYSES ..................................................................................... 8 
7.1 
Analysis Sets ................................................................................................................... 8 
7.1.1 
Screened Population.................................................................................................. 8 
7.1.2 
Safety Analysis Population ....................................................................................... 8 
7.1.3 
PD Analysis Population ............................................................................................ 8 
7.1.4 
Complete Analysis Population .................................................................................. 8 
7.2 
Baseline ........................................................................................................................... 8 
7.2.1 
Duration/Study Day/Time ......................................................................................... 9 
7.2.2 
Conventions for Missing and Partial Dates ............................................................ 10 
7.2.3 
Missing/Partial Start/Stop Date of Adverse Events and Concomitant Medications 10 
7.2.4 
Electrocardiogram Data .......................................................................................... 11 
7.2.5 
Unscheduled Visits ................................................................................................. 11 
7.3 
Conventions .................................................................................................................. 11 
7.3.1 
Decimal Places ........................................................................................................ 12 
7.4 
Derived Variables ......................................................................................................... 13 
7.4.1 
Area under the effect curve over 28 days (AUEC28) ............................................. 13 
7.4.2 
Maximum Effect (Emax) ........................................................................................ 13 
7.4.3 
BPI-SF variables ..................................................................................................... 13 
7.5 
Subject Disposition ....................................................................................................... 13 
7.6 
Protocol Deviations ....................................................................................................... 14 
7.7 
Baseline Comparability ................................................................................................. 14 
7.8 
Demographic data ......................................................................................................... 14 


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7.9 
Medical History ............................................................................................................ 14 
7.10 
Prior and Concomitant Medications ............................................................................. 14 
7.11 
Pharmacodynamic Analyses ......................................................................................... 15 
7.11.1 
Dexamethasone-induced HPA suppression ............................................................ 15 
7.11.2 
NPRS....................................................................................................................... 15 
7.11.3 
BPI-SF..................................................................................................................... 15 
7.11.4 
Area under the effect curve over 28 days and maximum effect ............................. 16 
7.12 
Safety Analyses ............................................................................................................. 17 
7.12.1 
Adverse Events ....................................................................................................... 17 
7.12.2 
Laboratory Data ...................................................................................................... 18 
7.12.3 
Vital Signs and Body Weight ................................................................................. 19 
7.12.4 
Electrocardiogram Data .......................................................................................... 20 
7.12.5 
Physical Examination.............................................................................................. 20 
7.12.6 
General Neurological and Targeted Neurological Examinations ........................... 20 
8 
INTERIM ANALYSIS ......................................................................................20 
9 
DATA SAFETY MONITORING BOARD ANALYSIS .................................20 
10 CHANGES TO PLANNED PROTOCOL ANALYSIS ...................................21 
11 LIST OF TABLES, FIGURES AND LISTINGS .............................................22 
12 REFERENCES ..................................................................................................30 
 
 
 


 
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1 LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
AE 
adverse event 
AUEC28 days 
area under the effect time curve at 28 days post dose 
BMI 
body mass index 
BPI-SF 
Brief Pain Inventory-Short Form 
bpm 
beats per minute 
CDISC 
Clinical Data Interchange Standards Consortium 
CI 
confidence interval 
ECG 
electrocardiogram 
Emax 
maximum effect 
EOS 
end of study 
ET 
early termination 
HbA1c 
Hemoglobin A1c 
HIV 
human immunodeficiency virus 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
milligram 
MRI 
magnetic resonance imaging 
NPRS 
Numeric Pain Rating Scale 
PD 
pharmacodynamic 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SD 
standard deviation 
T1 
Treatment 1 – Index injection 
T2 
Treatment 2 - Repeat injection 
TF 
transforaminal 
WBC 
white blood cells 
 
 


 
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2 INTRODUCTION 
This document details the planned statistical analyses for the Semnur Pharmaceuticals, Inc, 
protocol “SP-102-03” study titled “An Open-label, Single-arm Study to Characterize the 
Pharmacodynamics and Safety of Repeat Dose SP-102 (Dexamethasone Sodium Phosphate 
Injectable Gel) Administered by Epidural Injection in Subjects with Lumbosacral Radiculopathy.” 
The proposed analyses are based on the contents of the final version of the protocol (dated 08-
JUN-2018). 
This is an open-label, single-arm, repeat dose study to characterize the PD and safety/tolerability 
of SP-102 (10 mg dexamethasone) administered by epidural injection as transforaminal (TF) or 
interlaminar (IL) injection under fluoroscopic guidance in subjects with lumbosacral 
radiculopathy. 
Subjects meeting the eligibility criteria will be enrolled in the study and receive a single 2-mL 
epidural injection of SP-102 (10 mg dexamethasone) in T1 (index injection) and T2 (repeat 
injection), separated by 4 to 8 weeks. T2 will only be provided if a repeat injection is warranted 
and the subject continues to meet applicable study inclusion and exclusion criteria.  
 
3 STUDY OBJECTIVES 
3.1 Primary Objective 
The primary objective of the study is to characterize repeat dose pharmacodynamics (PD) of SP-
102 (10 mg dexamethasone) administered by epidural injection with respect to hypothalamic-
pituitary-adrenal (HPA) suppression using plasma cortisol levels, white blood cell count (WBC), 
and blood glucose. 
3.2 Secondary Objective 
The secondary objectives of the study are to: 
• Evaluate the safety and tolerability of single and repeat dose SP-102 (10 mg 
dexamethasone) administered by epidural injection in subjects with lumbosacral 
radiculopathy. 


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• Evaluate the analgesic effect on leg pain (as measured by the Numeric Pain Rating Scale 
[NPRS] in the affected leg) following the index (Treatment [T1]) and repeat (T2) 
injections. 
4 ENDPOINTS 
4.1 Pharmacodynamic Endpoints 
• Dexamethasone-induced HPA suppression as measured by: 
o Observed total blood cortisol levels, change from baseline cortisol levels, and percent 
change from baseline cortisol levels 
o Observed glucose levels, change from baseline glucose levels, and percent change from 
baseline glucose levels 
o Observed white blood cell counts, change from baseline white blood cell counts, and 
percent change from baseline white blood cell counts 
 
• NPRS (average leg pain and back pain) and BPI-SF 
• Change from T1 Day 0 and T2 Day 0 through Day 28 in NPRS (average leg pain and back 
pain) and BPI-SF over time following the index (T1) and repeat (T2) epidural injections, 
respectively 
• Percent change from T1 Day 0 and T2 Day 0 through Day 28 in NPRS (average leg pain and 
back pain) and BPI-SF following the index (T1) and repeat (T2) epidural injections, 
respectively 
4.2 Safety Endpoints 
• Incidence of treatment-emergent AEs (TEAEs) and serious adverse events (SAEs) 
• Change from baseline in clinical laboratory parameters, vital sign measurements, ECG 
findings, physical examination, general neurological examination findings, and targeted 
neurological examination parameters following each treatment. 
5 SAMPLE SIZE 
No formal statistical power calculation was performed for this study; the sample size is based on 
clinical and practical considerations. Enrollment will continue until 12 subjects have each 
completed two SP-102 injections (T1 and T2). 
6 RANDOMIZATION 


 
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This is an open-label study; there is no blinding. All subjects will receive SP-102 for each of the 
injections. 
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 Sets 
Subjects excluded from the analysis sets and the reason for their exclusion will be listed in 
Appendix 16.2. 
7.1.1 Screened Population 
This consist of subjects who signed the ICF and are assigned a study subject number. 
7.1.2 Safety Analysis Population 
The Safety Analysis population is defined as all enrolled subjects who receive at least one SP-
102 injection.  
7.1.3 PD Analysis Population 
The PD Analysis population is defined as all enrolled subjects who have a T1 period baseline PD 
result and at least 1 post-dose PD assessment result without any protocol deviations available in 
either T1 or T2.  
Major protocol violations that impact the PD analysis may lead to exclusion from the PD 
population. 
7.1.4 Complete Analysis Population 
The Complete Analysis population is defined as all enrolled subjects who receive only one SP-102 
injection who complete T1 – Day 28 plus those subjects who receive two SP-102 injections who 
complete T2 – Day 28.  
7.2 Baseline 


 
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Unless otherwise specified, baseline is defined as the last non-missing measurement taken prior to 
treatments T1 or T2 (reference start date). This includes screening or unscheduled assessments that 
would have been performed no earlier than 21 days before the reference start date. 
In the case where the last non-missing measurement and the reference start date coincide, that 
measurement will be considered pre-reference, but AEs and medications commencing on the 
reference start date will be considered post-reference. 
For laboratory tests, baseline is defined as the last measurement obtained during screening prior to 
T1. 
For vital signs parameters, an assessment performed on reference start date with time point marked 
as “pre-dose” will be considered as baseline for the given treatment period. 
Baseline ECG is the last measurement prior to the index injection. 
For physical exams, baseline is defined as the last assessment prior to T1 on Day 0. 
For General and Targeted Neurological Exam baseline for each treatment period is defined as the 
pre-dose assessment. 
 
For cortisol suppression, glucose, and white blood cell counts, baseline is defined as the last non-
missing value obtained prior to T1 or T2, which is T1/T2 Day 1 pre-dose measurement. 
For NPRS and BPI-SF, baseline is defined as the last non-missing value obtained prior to T1 or 
T2, which is T1/T2 Day 0 measurement. 
7.2.1 Duration/Study Day/Time  
There are two reference start dates, one for the index injection and one for the repeat injection. 
Study day will appear in every listing where an assessment date or event date appears. 
Study Day for assessments during the treatment period will be calculated for each treatment period 
using the dosing day for each period as the reference start date (that is, days during the T1 period 
should be calculated from Index dosing time, and days during T2 period should be calculated from 
repeat dosing time) and will be used to show start/stop day of assessments and events.  
• Therefore, if the date of the assessment/event is on or after the reference date then:  
Study Day = (date of assessment/event – reference date) + 1. 
Study day for assessments prior to start of treatment will use the index injection date as the 
reference date. 


 
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• Therefore, if the date of the assessment/event is prior to the reference date then:  
Study Day = (date of assessment/event – reference date).  
7.2.2 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). 
7.2.3 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: 
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. 
• 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. 
• 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: 
• If the stop date occurs on or after the start of study drug or the event/concomitant 
medication is ongoing, the start date will be imputed as the date of the first dose of study 
drug.  
• If the stop date occurs before the start of study drug, 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) 
• If the stop date occurs on or after the start of study drug or the event/concomitant 
medication is ongoing, and the year is the same as the year of first dosing the start date will 
be imputed as “01-Jan” of the same year or the date of the first dose of study drug 


 
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whichever is latest. If the year is different from the year of first dosing “01-Jan” will be 
used. 
• If the stop date occurs before the start of study drug, 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) 
• If the stop date occurs on or after the start of study drug 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 first dose of study drug in which 
case the date of first dose of study drug will be used.  
• If the stop date occurs before the start of study drug, the start date will be imputed as the 
first day of the month and year of the partial stop date. 
7.2.4 Electrocardiogram Data 
For ECG data recorded on continuous scales, if more than one value is recorded at a time point, 
the mean value rounded to the integer will be presented. For overall interpretation if more than one 
value is recorded, the most severe (worst case) of the respective readings will be taken. 
7.2.5 Unscheduled Visits 
Except for ET assessments, only scheduled post-baseline laboratory and vital signs values will be 
tabulated. Post-baseline repeat/unscheduled assessments will be disregarded, although these post-
baseline assessments will be listed in the relevant appendices to the CSR.  
For post-baseline PD, laboratory and vital sign data, if an Early Termination assessment falls 
between two visits and the visit prior to that ET visit has a valid assessment, then that ET 
assessment will be mapped to the subsequent visit within the treatment period. If the scheduled 
assessment prior to an ET assessment is missing, then the ET assessment will be mapped to that 
prior assessment. Assessments from T1 cannot be assigned to T2. 
7.3 Conventions 
All data listings, summaries, figures and statistical analyses will be generated using SAS version 
9.4 or higher1. 
Summaries will be presented by treatment (Treatment 1 and 2). Treatment periods (T1/T2) will be 
displayed as follows:  
 


 
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Treatment 1 
Treatment 2 
Overall 
 
Overall columns are to be included within the table shells as follows: 
Demography 
Overall 
Baseline 
Overall 
Disposition 
Overall 
PD 
Treatment 
AEs 
Treatment & overall 
Other safety 
Treatment 
 
Listings will be sorted in the following order subject, treatment period (T1/T2), parameter, and 
study day unless otherwise stated.  
Continuous variables will be summarized by the number of non-missing observations, mean, 
median, standard deviation, and minimum and maximum.  
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.  
7.3.1 Decimal Places 
Decimal places for derived data 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.  
Derived data where it is known in advance the result will be an integer for example day, month, 
year, number of days and total scores (for rating scales) 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.  


 
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P- Values will be quoted to 3 decimal places. P-values < 0.001 will be presented as p<0.001. Where 
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. 
7.4 Derived Variables 
7.4.1 Area under the effect curve over 28 days (AUEC28) 
AUEC28 days is defined as the change from baseline (for cortisol, glucose, and WBC) and 
calculated using linear trapezoidal summation from pre-dose to Day 28 in each treatment period. 
AUEC28 analyses for the for cortisol, glucose, and WBC will be based on the assumption that the 
baseline assessment take place at time zero. Only scheduled and ET visit assessments will be 
included in the computation. If the actual time is not recorded the nominal time will be used.  
Cortisol, glucose, and WBC ET assessments will be mapped to Day 28 and AUEC28 will then be 
computed. 
If a subject has no pre-dose value, AUEC28 will not be calculated. In the case where a subject has 
two values recorded at the same time, the two scores will be averaged. 
7.4.2 Maximum Effect (Emax) 
Emax is the maximum increase from baseline (pre-treatment level, T1 or T2) in glucose level and 
WBC count or the maximum decrease in cortisol levels over the 28 days post dose in each 
treatment period. An Emax value will be calculated for cortisol, glucose, and WBC for each 
treatment period (T1/T2). 
7.4.3 BPI-SF variables 
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) 
7.5 Subject Disposition 
Subject disposition will be summarized as follows:  
• The number of subjects that were screened, number that failed screening, and number in 
each analysis set will be summarized by treatment period and overall using the Screened 
Population.  


 
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• The number of early discontinuations and the reasons for withdrawals will be summarized 
by treatment period (T1/T2) and overall (T1 and T2) for the Safety Analysis population. 
• The number of subjects who complete each treatment period of the study and the number 
of subjects present at each scheduled visit will be summarized by treatment period for the 
Safety Analysis population.  
7.6 Protocol Deviations 
Protocol deviations will be adjudicated into major and minor. A listing of both major and minor 
protocol deviations will be provided. 
7.7 Baseline Comparability 
Demographics and baseline characteristics will be assessed in a descriptive manner, and no formal 
statistical testing will be performed. 
Standard continuous or categorical variable summaries will be presented for all subjects for the 
following variables based on the Safety Analysis population. 
7.8 Demographic data 
The following demographic variables will be summarized for all subjects: Age (years), gender, 
childbearing potential, race, ethnicity, height (cm), weight (kg), BMI (kg/m2), Straight leg raise, 
Femoral stretch test, Hepatitis B Surface Antigen, Hepatitis C Virus Antibodies, HIV-1 Antibody, 
and HIV-2 Antibody. 
7.9 Medical History 
Summaries of previous and ongoing conditions at screening will be presented. Conditions will be 
presented by Medical Dictionary of Regulated Activities (MedDRA) primary system organ class 
and preferred term. 
7.10 Prior and Concomitant Medications 
Prior medications are defined as all medications starting and ending before the first dose of study 
drug. Prior medications will be summarized for all subjects. Concomitant medications are defined 
as medications taken on or after the date of the index injection through the EOS/ET participation. 
Concomitant medications will be summarized by treatment period (T1/T2) using ATC Level 2 and 
listed. If the onset date of a concomitant medication is on or post the index injection dosing date 
but before the repeat injection dosing date, it will be considered as occurring during T1; otherwise, 


 
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the onset date of concomitant medication on or post the repeat injection date will be considered as 
occurring in T2. If a medication is taken during both treatment periods it will be counted in both 
periods. 
7.11 Pharmacodynamic Analyses 
All comparisons between treatments will be analyzed in log scale but will be reported as ratios 
with 90% confidence intervals for the difference. All PD analyses will use the PD Analysis 
population as the primary analysis population.  
7.11.1 Dexamethasone-induced HPA suppression 
Blood samples for PD will be collected at screening, for T1 at pre-dose (baseline), Days 1, 2, 3, 4, 
5, 8, 15, and 28, for T2 at pre-dose (baseline), Days 1, 2, 3, 4, 5, 8, 15 and 28.  
Dexamethasone-induced HPA suppression will be evaluated by using the observed plasma cortisol 
level, blood glucose levels, and WBC count.  Plasma cortisol levels, plasma WBC counts, and 
fasting plasma blood glucose levels will be summarized by treatment group and day using 
descriptive statistics for observed, change from baseline, and percent change from baseline values. 
Summary tables will include, the arithmetic mean, standard deviation, coefficient of variation, 
minimum, maximum, median, and geometric means will also be reported. 
7.11.2 NPRS   
NPRS assessments will be done at screening, for T1 at Days 0 (baseline), 1, 2, 3, 4, 5, 8, 15, and 
28. For T2, NPRS will be done at Days 0 (baseline), 1, 2, 3, 4, 5, 8, 15, and 28. Baseline for each 
treatment period is the NPRS score taken before the injection on Day 0. 
The NPRS is an 11-point scale (0 to 10-point scale where 0 is no pain and 10 is worst pain 
imaginable) that allows the subject to rate the severity of their pain intensity at various points in 
time. The subject will use the NPRS to record their current pain, average pain in the past 24 hours, 
and worst pain in the past 24 hours for both their affected leg(s) and back pain.  The NPRS 
assessments will be summarized by treatment period and day using descriptive statistics for 
observed, change from baseline, and percent change from baseline values.   
7.11.3 BPI-SF 
BPI-SF will be collected for T1 at Days 0 (baseline), 1, 2, 3, 4, 5, 8, 9, and 10. For T2, NPRS will 
be done at Days 0 (baseline), 1, 2, 3, 4, 5, 8, 15, and 28. Baseline for each treatment period is the 
BPI-SF score taken before the injection on Day 0.  


 
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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 also has items that address reactive pain components, including 
depression, suffering, and perceived availability of relief. Two BFI-SF scales will be derived from 
the BPI-SF responses: the pain severity score and pain interference score.  The two BPI-SF 
parameters will be summarized by treatment period and day using descriptive statistics for 
observed, change from baseline, and percent change from baseline values. 
7.11.4 Area under the effect curve over 28 days and maximum effect 
The area under the effect curve over 28 days (AUEC28) and maximum effect (Emax) following 
the T1 (index) and T2 (repeat) injections will be calculated for cortisol levels, WBC counts, and 
fasting blood glucose levels.   
AUEC28 will be compared for cortisol following index and repeat injections within the same 
subject to conclude whether or not repeat injection results in more pronounced cortisol 
suppression. This will be done using a two-sided paired T-test with the null mean being zero. 
AUEC28 and Emax will be compared for cortisol, glucose, and WBC between index injection 
(treatment 1) and repeat injection (treatment 2) using a mixed model analysis of variance using 
PROC MIXED with a fixed effect for treatment (treatment 1 and 2) and a random effect for subject. 
Estimates and 90% confidence intervals (CIs) will be first constructed in the logarithmic scale.  
The response variable will be the change from pre-dose of each PD parameter. Treatment 
comparisons will be performed between treatments T1 and T2 with T2 being the reference. By 
taking anti-logarithms, estimates and CIs for the geometric means and ratios of geometric means 
will be calculated. All CIs will be 2-sided.  
The statistical model will have the following form: 
 
The following SAS code will be used to run the model; 
 
 
 
 
 
 
 
 
 


 
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The following SAS code will be used to calculate the geometric means, geometric ratio and its 
confidence interval: 
 
 
 
 
 
 
 
 
 
 
 
 
 
A lack of effect of repeat injection on the PD will be concluded if the 90% CIs for the ratio of T2 
(repeat injection; Test) to T1 (index; Reference) for both AUEC28 days and Emax are completely 
contained within the range of 80 to 125%. 
7.12 Safety Analyses 
The safety analyses will be presented by the treatment period for the Safety Analysis population. 
7.12.1 Adverse Events  
All AEs will be coded using the most current version of MedDRA. TEAEs and SAEs will be 
summarized descriptively for each treatment period. 
 
A treatment emergent adverse event (TEAE) phase is defined as meeting either of the following 2 
criteria: 
• Any AE that has an onset on or after the index injection and within (after) 30 days of the 
last study treatment. 
• Any pre-existing AE that has worsened in severity on or after the index injection and within 
(after) + 30 days of the last injection.  
TEAEs for each treatment period, will be assessed as follows:  
• A TEAE will be assigned to the treatment received immediately before onset. 
• If the severity of a TEAE increases in a later period the TEAE at the increased severity will 
be assigned to the treatment received immediately before the increase in severity. 


 
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Onset date of adverse events on or post visit 3 but before visit 11 were considered as occurring 
during T1; otherwise onset date of adverse events on or post visit 11 were considered as occurring 
during T2 
A treatment-related AE is defined as an AE as being possibly, probably or related to the study 
drug. If an AE has missing relationship it is assumed to be related to the study drug for analysis 
purposes. 
Severity is classified as mild/moderate/severe/life-threatening/death (last two grades applied for 
SAE). If a subject reports AEs more than once within a SOC/PT, the AE with the worst-case 
severity will be used in the corresponding severity summaries. TEAE summary tables (except the 
overall summary table) will be presented by severity and overall. 
The following tables will be presented by severity and overall for AEs: 
• Overall incidence and the number of AEs, SAEs, TEAEs leading to withdrawal. 
• Treatment-Emergent Adverse Event by System Organ Class and Preferred Term 
• Related Treatment-Emergent Adverse Event by System Organ Class and Preferred Term 
• Serious Treatment-Emergent Adverse Events by System Organ Class and Preferred Term 
• Serious Treatment Related Treatment-Emergent Adverse Events by System Organ Class 
and Preferred Term 
• Treatment Discontinued Treatment-Emergent Adverse Events by System Organ Class 
and Preferred Term  
• Summary of Treatment-Emergent Adverse Events Leading to Death 
All AEs will be listed. 
7.12.2 Laboratory Data 
Descriptive statistics of the observed values and change from baseline (continuous data) will be 
presented by treatment period and visit (Screening, T1 – Day 5, T1 – Day 28, T2 – Day 5, and T2 
– Day 28 (Visit 19/EOS/ET)) for each hematology (Hemoglobin, hematocrit, red blood cell count, 
WBC count (with differential [lymphocytes, neutrophils, eosinophils, basophils, and monocytes]), 
and platelet count), serum chemistry (albumin, alkaline phosphatase, AST, ALT, direct bilirubin, 
total bilirubin, blood urea nitrogen, calcium, chloride, creatine kinase (Screening only), creatinine, 
gamma-glutamyl transferase, glucose, lactate dehydrogenase, potassium, sodium, and uric acid), 
and urinalysis (Dipstick analysis: color, turbidity, specific gravity, pH, glucose, protein, ketones, 
urobilinogen, bilirubin, blood nitrate, leukocyte esterase, and microscopic examination when 


 
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indicated by dipstick results) parameter. Each measurement (continuous data) will be classed as 
below, within, or above normal range, based on ranges supplied by the laboratory used. Shift tables 
in relation to the normal range from baseline to each follow-up visit will be presented. 
The following lab parameters will be listed only. HbA1c, HIV, hepatitis B, and hepatitis C at 
Screening. Coagulation tests at Screening or Baseline: activated PTT, PT, INR, serum pregnancy 
test at Screening, urine pregnancy test at Baseline and at Visit 11 (T2 – Day 0), and MRI. 
A listing of any clinically significant laboratory measurements recorded throughout the study will 
be presented. 
7.12.3 Vital Signs and Body Weight 
Descriptive statistics for observed values and changes from baseline in the following vital signs 
will be presented by treatment period and visit for T1 at Days 0 (baseline), 1, 2, 3, 4, 5, 8, 15, and 
28, for T2 at Days 0 (baseline), 1, 2, 3, 4, 5, 8, 15, and 28. 
• Systolic blood pressure (mmHg) 
• Diastolic blood pressure (mmHg) 
• Heart rate (bpm)  
• Weight (kg) 
Vital signs will be monitored within 15 min prior to the SP-102 injection, approximately every 5 
min during the procedure (prior to syringe removal), and approximately every 15 min after for 60 
min after the procedure. For Day 1 in both treatment periods, vital signs for three timepoints will 
be summarized:  
Pre-injection: this is the value taken at 15 mins prior to the injection 
During injection: this is the mean of the values taken during the injection procedure 
Post-injection: this is the mean of the values recorded post injection 
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 


 
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Heart rate 
< 60 or > 100 bpm 
 
Vital signs data will also be listed. 
7.12.4 Electrocardiogram Data 
Since ECGs are collected in triplicates, the values will be averaged at each visit. ECGs will be 
assessed for T1 at Day 0 (baseline), Day 28, for T2 at Day 28. Descriptive statistics for observed 
values and changes from baseline in the following ECG variables will be tabulated at each follow-
up:  
• Heart rate (bpm) 
• PR interval (ms) 
• RR interval (ms)  
• QRS duration (ms)   
• QT interval (ms)  
• QTc interval (ms)  
Shift tables in relation to the overall interpretation (Normal, Abnormal NCS, and Abnormal CS) 
from baseline to each follow-up visit will be presented. 
7.12.5 Physical Examination 
A physical examination will be done at Screening, T1 – Day 0, T1 – Day 28, and T2 – Day 28 
(Visit 19/EOS/ET). The results of the body systems within the physical examination data be 
summarized by treatment period and listed. A shift table will also be provided. 
7.12.6 General Neurological and Targeted Neurological Examinations 
General and targeted neurological examinations will be performed pre-dose and post dose on T1 
– Day 1, pre-dose and post dose on T2 – Day 1, and on T2 – Day 28 (Visit 19/EOS/ET). The 
results will be summarized and listed. 
 
8 INTERIM ANALYSIS 
No interim analyses are planned.  
9 DATA SAFETY MONITORING BOARD ANALYSIS 


 
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No data safety monitoring board (DSMB) analyses are planned. 
10 CHANGES TO PLANNED PROTOCOL ANALYSIS 
In the protocol, it is stated that: “No formal statistical hypothesis testing will be performed in this 
study, however descriptive statistics will be presented”. However, given that inferential analysis 
will be carried out on the PD data, this statement is disregarded.  
 
 


 
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11 LIST OF TABLES, FIGURES AND LISTINGS 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 




 
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12 REFERENCES 
1. SAS Institute Inc.  The SAS System, Version 9.4.  Cary, NC, SAS Institute Inc. 2012.