Conditions: Abdominoplasty
Keywords: pain, neurotoxin
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 23
Healthy volunteers: no

Brief summary:
To determine the safety and efficacy of single intra-operative treatment of Botulinum Neurotoxin Serotype E (EB-001) intramuscular (IM) injections into the Rectus Abdominus (RA) in participants undergoing abdominoplasty.

Detailed description:

Arms:
arm 1: Placebo (sterile saline solution 0.9% Sodium Chloride Injection) injected into RA muscles during abdominoplasty surgery. arm 2: Single botulinum neurotoxin serotype E Dose 1 injection into RA muscles during abdominoplasty surgery. arm 3: Single botulinum neurotoxin serotype E Dose 2 injection into RA muscles during abdominoplasty surgery. arm 4: Single botulinum neurotoxin serotype E Dose 3 injection into RA muscles during abdominoplasty surgery.

Interventions: intervention 1: Botulinum Neurotoxin Serotype E intervention 2: Placebo
Intervention descriptions: intervention 1: Single botulinum neurotoxin serotype E injection into RA muscles during abdominoplasty surgery. intervention 2: Placebo (sterile saline solution 0.9% Sodium Chloride Injection) injected into RA muscles during abdominoplasty surgery.

Protocol document:
Prot_000.pdf: 
 
NCT03429556 
 
Study ID: EB001-ABD201 
 
Title: A Phase 2 Study to Evaluate Safety and Efficacy of EB-001 Intramuscular (IM) Injections 
in Reducing Musculoskeletal Pain in Subjects Undergoing Elective Abdominoplasty Surgery 
 
Protocol Amendment 4: 28 September 2018 
 


Protocol 
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Amendment 
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IND 
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Page 1 of 103 
Confidential / Trade Secret 
 
 
 
 
 
 
 
 
CLINICAL STUDY PROTOCOL 
 
 
 
 
A Phase 2 Study to Evaluate Safety and Efficacy of EB-001 
Intramuscular 
(IM) 
Injections 
in 
Reducing 
Musculoskeletal 
Pain 
in 
Subjects 
Undergoing 
Elective 
Abdominoplasty 
Surgery 
Study Number: EB001-ABD201 
IND Sponsor: Bonti, Inc. 
Version 
Number: 
5.0 
Amendment: 
4 
Amendment 4 Date: 
28 
September, 
2018 
Amendment 3 Date: 
09 Ma
y, 2018 
Amendment 2 Date: 
20 April, 
2018 
Amendment 1 Date: 
16 
March, 
2018 
Original Protocol Date: 
09 
February, 2018 
 
 
CONFIDENTIALITY STATEMENT 
The information in this document contains trade secrets and commercial information that 
are confidential and may not be disclosed unless such disclosure is required by applicable 
laws and regulations. In any event, persons to whom the information is disclosed must be 
informed that the information is confidential and may not be further disclosed by them. 
These restrictions on disclosure will apply equally to all future information supplied to you 
which is indicated as confidential. 


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Amendment 4 changes from Amendment 3 
include: 
• As per FDA 
feedback 
o Update study 
design with regard to dosing rationale, dosing regimen, and 
sample size 
 
 
o Apply study stopping criteria to all cohorts and stages of the study 
o Include statement on how to manage subjects who develop adverse 
effects 
indicative of spread of toxin 
o Update 
dosage of allowed rescue medication 
o Add criteria of when opioid 
rescue medications can be administered 
o Add muscle relaxants as 
prohibited medication 
o Specify that the subject, investigator and site staff are blinded, only sponsor is 
unblinded 
• Change in allowable use 
of rescue medication during surgery, and in the first 12 
hours 
following injection. 
• Administrative changes are to: 
o Update of title 
page and 
headers 
throughout 
o Update 
of 
typographic 
errors 


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Amendment 3 changes from Amendment 2 
include: 
• Increase of one additional cohort in Stage 1 from 3 to 4. 
 
 
• Increase of sample size of optional cohort in Stage 1 from 8 to up to 42 subjects. 
• Administrative changes are to: 
o Update of title 
page and 
headers 
throughout 
o Update 
of 
typographic 
errors 


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Amendment 2 changes from Amendment 1 
include: 
• Study 
design change of Stage 1 from a double-blind manner to a single-blind manner. 
• Change of sample size of 
each cohort in Stage 1 from 6 to 8 (2 additional 
placebo 
subjects: 1 in the sentinel group and 1 in the rest 
of the cohort. 
• Handling 
participant exceeding allowed 
rescue 
medication separately from 
early 
terminated 
participant 
• Administrative changes are to: 
o Update of title page and headers 
throughout 
o Update 
of 
typographic errors 


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Amendment 1 
changes from original 
protocol 
include: 
• Addition of secondary efficacy measures: Over 
the period of 
time X to 96 
hours post- 
surgery 
(AUC
t-96), whereas X is any 
time during confinement 
• Revision of NPRS-A: Pain assessment after sitting 
up in the bed unassisted at an 
angle of approximately 45 degrees or more, swinging legs out, putting 
feet down, 
standing up, and walking 
approximately 10 feet 
 
 
• Revision and addition of exclusion criteria 
6. Unacceptable risk of deep vein 
thrombosis (DVT) as deemed 
by the investigator 
7. Past major surgery (more than 45 minutes) within the last 6 months 
8. History of blood clots, 
either 
DVT or 
pulmonary 
embolism 
9. Current or past malignancies (excluding 
skin c
ancer, but not melanoma) within the 
last 12 months 
• Addition 
of NPRS-A data 
collection term prior 
to rescue medication usage: In the 
event subjects can 
not 
perform 
NPRS-A due to intolerable pain, this assessment may 
be 
omitted. 
• Addition 
of warm packs for upper back pain 
• Addition 
of assessment window of ±2 hours in various assessments. 
• Addition 
of compression 
calf sleeves 
• Revision of 
NPRS and 
NPRS-A collection 
time: NPRS and NPRS-A scores will be 
recorded by Subjects daily, in 
the morning (10:00 ±4 hours), in a take-home diary 
beginning on the day after discharge (Day 5) through EOS/ET. 
• Administrative changes are to: 
o Update of title 
page and 
headers 
throughout 
o Update 
of 
typographic 
errors 


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STATEMENT OF COMPLIANCE 
 
By signing below, I confirm that I have read this 
protocol and agree: 
• to assume responsibility 
for the proper conduct of the study at this site, 
• to conduct the study according to the procedures described in this 
protocol and any 
future 
amendments, 
• not to implement any 
deviation from, or changes 
to, 
the protocol without 
agreement of 
the sponsor and written approval 
from the Institutional Review Board 
or Independent Ethics Committee, 
except where 
necessary 
to eliminate 
an 
immediate 
hazard 
to subject(s), and 
• that I am aware of and will comply with all applicable regulations and guidelines on 
clinical trials, Good Clinical Practice (GCP), and protection of human subjects 
 
 
 
 
 
 
 
 
 
 
Investigator 
Printed 
Name 
Signature 
Date 


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TABLE OF CONTENTS 
TABLE OF CONTENTS 
.................................................................................................................. 8 
LIST OF TABLES 
.................................................................................................................................... 
11 
LIST OF FIGURES 
....................................................................................................................... 
12 
LIST OF ABBREVIATIONS AND GLOSSARY OF TERMS ............................................................... 
13 
1 KEY ROLES 
............................................................................................................................... 
33 
2 INTRODUCTION 
.................................................................................................................. 
34 
 
 
 
 
 
 
2.2 Rationale ............................................................................................................................. 
37 
2.2.1 
Study Rationale 
.......................................................................................................... 
37 
2.3 Potential Risks and Benefits 
........................................................................................... 
38 
2.3.1 Known Potential Risks 
.................................................................................................... 
38 
2.3.2 Known Potential Benefits........................................................................................... 
41 
3 OBJECTIVES AND PURPOSE 
................................................................................................ 
41 
4 STUDY DESIGN AND ENDPOINTS 
....................................................................................... 
42 
4.1 Description of the Study Design 
.................................................................................... 
42 
4.2 Study Endpoints 
............................................................................................................. 
46 
4.2.2 Primary Efficacy Endpoint 
.......................................................................................... 
46 
4.2.3 Secondary Efficacy Endpoints 
.................................................................................... 
47 
5 STUDY ENROLLMENT AND WITHDRAWAL 
............................................................................ 
47 
5.1 Participant Inclusion Criteria ......................................................................................... 
48 
5.2 Participant Exclusion Criteria 
......................................................................................... 
48 
5.3 Strategies for Recruitment and Retention 
........................................................................ 
49 
 
 
 
 
 
 
 
 
 
 
 
 


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5.4 Participant Withdrawal or Termination 
............................................................................ 
50 
5.4.1 Reasons for Withdrawal or Termination 
....................................................................... 
50 
5.4.2 Handling of Participant Withdrawal or Termination 
.................................................... 
50 
5.4.3 Handling of Participant Exceeding Allowed Rescue Medication................................ 
51 
5.5 Replacement of Subjects 
............................................................................................... 
51 
5.6 Premature Termination or Suspension of Study ........................................................... 
51 
 
 
 
 
 
 
 
6.1.5 Dosing and Administration 
............................................................................................ 
52 
6.1.6 Route of Administration 
................................................................................................ 
53 
6.1.7 Starting Dose and Dose Escalation Schedule 
............................................................. 
53 
6.1.8 Dose Adjustments/Modification/Delays in Stage 1 
................................................... 
53 
6.1.9 Duration of Treatment ....................................................................................................... 
53 
6.1.10 Tracking of Study Vials and Dose 
............................................................................... 
53 
6.1.11 Replacement Procedures for Investigational Medicinal Product 
............................... 
53 
6.2 Investigational Product Accountability Procedures 
....................................................... 
53 
 
7.2 Use of Rescue Medication and Assessment of Sedation and Respiratory Status 
.......... 
64 
7.3 Laboratory Procedures/Evaluations 
.................................................................................. 
65 
7.3.1 Clinical Laboratory Evaluations 
..................................................................................... 
65 
7.3.2 Specimen Preparation, Handling, and Storage 
............................................................ 
65 
7.3.3 Specimen Shipment 
................................................................................................... 
65 
7.3.4 Volume of Blood Collected 
........................................................................................ 
66 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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7.5 Concomitant Medications and Treatments 
...................................................................... 
67 
7.6 Prohibited Medications, Treatments, and Procedures 
.................................................... 
68 
7.7 Subject Restrictions 
....................................................................................................... 
68 
 
8.1 Specification of Safety Parameters ................................................................................... 
68 
8.1.1 Definition of Adverse Events (AE) 
.............................................................................. 
69 
8.1.2 Definition of Serious Adverse Events (SAE) ............................................................... 
69 
8.1.3 Definition of Unanticipated Problems (UP) ............................................................... 
71 
8.2 Classification of an Adverse Event 
.................................................................................... 
72 
8.2.1 Severity of Event 
............................................................................................................ 
72 
8.2.2 Relationship to Study Agent 
.......................................................................................... 
72 
8.2.3 Expectedness 
............................................................................................................. 
73 
8.3 Time Period and Frequency for Event Assessment 
and Follow-up 
................................ 
73 
8.4 Reporting Procedures 
........................................................................................................ 
74 
8.5 Adverse Event Reporting ............................................................................................... 
74 
8.5.1 Serious Adverse Event Reporting 
............................................................................... 
74 
8.5.2 Reporting of Pregnancy 
............................................................................................. 
76 
8.6 Study Halting Rules 
........................................................................................................ 
77 
8.7 Safety Oversight 
................................................................................................................. 
77 
8.8 Risk Management of Prolonged Respiratory Compromise 
............................................ 
77 
9 CLINICAL MONITORING AND COMPLIANCE....................................................................... 
78 
10 STATISTICAL CONSIDERATIONS 
.............................................................................................. 
78 
10.1 Statistical and Analytical Plans 
....................................................................................... 
78 
10.2 Statistical Hypotheses 
.................................................................................................... 
78 
10.3 Analysis Populations 
...................................................................................................... 
79 
10.4 Description of Statistical Methods 
................................................................................. 
79 
10.4.1 General Approach 
...................................................................................................... 
79 
10.4.2 Analysis of the Primary Efficacy Endpoint(s) ............................................................. 
80 
10.4.3 Analysis of the Secondary Endpoint(s) ...................................................................... 
80 
 
 
 
 
 
 
 
 
 
 


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10.5 Sample Size 
......................................................................................................................... 
84 
10.6 Measures to Minimize Bias 
............................................................................................ 
84 
10.6.1 Enrollment/ Randomization/ Blinding Procedures 
...................................................... 
84 
10.6.2 Evaluation of Success of Blinding 
............................................................................... 
85 
10.6.3 Breaking the Study Blind/Participant Code ............................................................... 
86 
11 SOURCE DOCUMENTS AND ACCESS TO SOURCE DATA/DOCUMENTS 
.................................. 
86 
12 QUALITY ASSURANCE AND QUALITY CONTROL 
.................................................................... 
87 
13 ETHICS/PROTECTION OF HUMAN SUBJECTS 
...................................................................... 
87 
13.1 Ethical Standard 
................................................................................................................. 
87 
13.2 Institutional Review Board ................................................................................................ 
87 
13.3 Informed Consent Process 
................................................................................................. 
88 
13.4 Participant and Data Confidentiality 
.............................................................................. 
88 
13.4.1 Research Use of Stored Human Samples or Data 
........................................................ 
88 
13.5 Future Use of Stored Specimens ................................................................................... 
89 
13.6 Protocol Amendments and Study Termination 
................................................................ 
89 
14 DATA
 HANDLING AND RECORD KEEPING 
........................................................................... 
89 
14.1 Data Collection and Management Responsibilities 
....................................................... 
89 
14.2 Study Records Retention and Availability 
...................................................................... 
90 
14.3 Protocol Deviations 
........................................................................................................ 
90 
14.4 Publication and Data Sharing Policy 
.................................................................................. 
90 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Table 3 
Likely Symptoms of Botulinum Tox
in Poisoning or Overdose .......................... 
40 
 
LIST OF TABLES 
 
 
 


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Table 4 
Toxicity Criteria 
................................................................................................. 
45 
Table 5 
Total Blood Volume Collected for Each Patient 
.................................................. 
66 
Table 6 
Criteria for Clinically Notable ECG Interval Abnormalities 
............................... 
82 


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LIST OF ABBREVIATIONS AND GLOSSARY OF TERMS 
Term 
Definition 
AE 
adverse 
event 
ALT (SGPT) 
alanine aminotransferase (= serum glutamic 
pyruvic transaminase) 
ANOVA 
Analysis of Variance 
ATC 
Anatomical Therapeutic 
Chemical 
AST (SGOT) 
aspartate aminotransferase (= serum glutamic 
oxaloacetic 
transaminase) 
AUC 
Area 
under 
the curve 
BMI 
Body Mass Index 
BoNT 
botulinum 
neurotoxin 
BoNT/A 
botulinum 
neurotoxin serotype A 
BoNT/E 
botulinum 
neurotoxin serotype E 
BP 
blood 
pressure 
BUN 
blood urea nitrogen 
CBL 
change 
from 
baseline 
CFR 
Code of Federal Regulations 
CMP 
clinical monitoring plan 
CRF 
case report 
form 
CRO 
Contract 
Research 
Organization 
DAS 
digital abduction score 
DVT 
deep vein 
thrombosis 
EB-001 
botulinum neurotoxin serotype E drug product 
ECG 
electrocardiogram 
eCRF 
electronic case 
report 
form 
 
 
 
EDC 
electronic 
data capture 
EOS 
end of study 
ET 
early 
termination 
EU 
European Union 
FDA 
Food and Drug Administration 
FEV1 
forced expiratory volume 1 
FVC 
forced vital capacity 
GCP 
Good Clinical Practice 
 


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Term 
Definition 
GGT 
gamma-glutamyl 
transferase 
GLP 
Good Laboratory 
Practices 
GMP 
Good 
Manufacturing Practices 
HBsAg 
hepatitis B surface antigen 
HC 
heavy chain 
HDL 
high 
density lipoprotein 
HEENT 
head, eye, ea
r, nose, throat 
HIV 
human immunodeficiency virus 
HR 
heart 
rate 
HSA 
human serum albumin 
ICF 
informed consent form 
ICH 
International Conference on Harmonization 
ICH E6 
International Conference on Harmonization Guidance for Industry, 
Good Clinical Practice: Consolidated Guidance 
IEC 
independent 
ethics 
committee 
IM 
Intramuscular 
IRB 
institutional review board 
IUD 
intrauterine 
device 
LC 
light chain 
LDH 
lactate 
dehydrogenase 
LDL 
low density lipoprotein 
M 
Molar 
MCH 
mean cell 
hemoglobin 
MCHC 
mean cell 
hemoglobin concentration 
MCV 
mean (red) cell volume 
MedDRA 
Medical 
Dictionary 
for Regulatory Activities 
mITT 
modified Intent 
to Treat 
mL 
Milliliter 
 
 
 
Msec 
Milliseconds 
NA 
not applicable 
Ng 
nano 
gram 
NPRS 
numerical 
pain rating scale 
l
 
 


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Term 
Definition 
NPRS-A 
NPRS administered after 
an activity 
NOAEL 
no observable adverse effects 
limit 
OHRP 
Office for Human Research Protections 
PACU 
post-anesthesia 
care 
unit 
PCV 
packed cell volume 
PI 
principal 
investigator 
PFT 
pulmonary 
function test 
PGA 
patient global 
assessment 
PM 
pectoralis 
major 
 
 
 
PP 
Per 
Protocol 
PR interval 
time between 
the onset of atrial 
depolarization and the onset of 
ventricular 
depolarization 
PRN 
as-needed 
RA 
Rectus abdominus muscle 
RBC 
red 
blood cell 
RDW 
red (cell) distribution width 
RR interval 
time elapsed 
between 
two consecutive R-waves 
QRS duration 
the interval 
from the beginning 
of the Q wave to 
the 
termination 
of 
the S wave, representing the time for ventricular depolarization 
QT interval 
interval representing the time for 
both ventricular 
depolarization 
and 
repolarization to occur 
QTc 
corrected QT 
(interval) 
QTcB interval  
QTc
 interval using Bazett’s correction (msec) = QT/(RR)½, where the 
QT interval is measured in msec and the RR interval is measured in 
seconds 
QTcF interval  
QTc
 interval using 
Fridericia’s correction (msec) = 
QT/(RR)⅓, where 
the QT interval is measured in msec and the RR interval is 
measured in seconds 
SAE 
serious 
adverse 
event/experience 
SAP 
statistical analysis plan 
SD 
Standard 
Deviation 
SNAP 
synaptosomal-associated 
protein 
SOT 
spread of toxin 
SRC 
Safety 
Review 
Committee 
 
 


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Term 
Definition 
SUSAR 
suspected 
unexpected 
serious adverse 
reactions 
SVC 
slow vital capacity 
RR interval 
time elapsing 
between two consecutive R waves in the 
electrocardiogram. It is 
used to assess 
the ventricular rate. 
TEAE 
treatment 
emergent 
adverse 
event 
µg 
Microgram 
UP 
unanticipated 
problem 
US 
United States 
WBC 
white 
blood cell 
(Leukocyte) 
WHO 
World Health Organization 


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Study 
Number: 
EB001-ABD201 
PROTOCOL 
SUMMARY 
 
Study 
Title: 
A Phase  2 Study to Evaluate Safety and Efficacy of EB-001 Intramuscular (IM) Injections in 
Reducing 
Musculoskeletal Pain in 
Subjects Undergoing Elective Abdominoplasty 
Surgery 
 
Investigational Drug 
Product: 
EB-001 (Botulinum 
Neurotoxin Serotype E, 
BoNT/E) for 
injection. 
 
Study 
Objectives: 
Safety Objective: To determine the safety and tolerability of  a single intraoperative 
treatment of EB-001 IM injections into the rectus abdominus (RA) muscles in subjects 
undergoing 
elective abdominoplasty surgery. 
 
Efficacy Objective: To evaluate the efficacy of intraoperative administration of EB-001 IM 
into the RA muscles in reducing the pain and use of rescue pain medications in subjects 
undergoing 
elective abdominoplasty surgery. 
 
Phase of Trial: 
Phase 2 
 
Clinical 
Hypothesis: 
Safety:  A single treatment of EB-001 IM injected into the RA muscles has an acceptable 
safety and tolerability profile at the tested doses in subjects undergoing  elective 
abdominoplasty 
surgery. 
 
Efficacy: A single treatment of EB-001 IM injected into the RA muscles reduces post-surgical 
musculoskeletal pain in subjects undergoing elective abdominoplasty surgery, at one or 
more of the 
doses tested in 
the study. 
 
Study 
Population: 
Healthy males or females 23 to 55 years of age, inclusive, undergoing elective 
abdominoplasty surgery (Full length plication from xyphoid to pubis, removal of skin/fat 
flap) 
under general anesthesia (endotracheal 
or otherwise) without liposuction. 
 
 
 
 
 
 
 
Outcome 
Measures: 
 
 
 


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Efficacy 
Measures: 
Primary 
Efficacy Measures: 
• Area under the curve (AUC) of subject’s assessment of pain using the Numeric Pain 
Rating Scale (NPRS) between 
12 and 
96 
hours post-surgery (AUC
12-96). 
Secondary Efficacy 
Measures: 
• AUC assessment of overall pain profile using NPRS: 
o Over the first 96 hours post-surgery (AUC
0-96)  
o Over the first 72 hours post-surgery (AUC
0-72)  
o Over the first 48 hours post-surgery (AUC
0-48)  
o Over the first 24 hours post-surgery (AUC
0-24) 
o Over the period of 12 to 24 hours post-surgery (AUC
12-24) 
o Over the period of time  X to 96 hours post-surgery (AUC
t-96), whereas  X is any 
time 
during confinement 
• Pain assessment at rest after discharge using 
NPRS at Days 6 through 
29. 
• Pain assessment after sitting up in the bed unassisted at an angle of approximately 
45 degrees or more, swinging legs out, putting feet down, standing up, and walking 
approximately 10 feet using NPRS-A (NPRS administered after an activity) over the 
first 96 hours and at Days 8, 15, 29. 
• Patient global assessment (PGA) of pain control 
• Use of 
rescue 
medications over various 
postsurgical periods 
 
Study 
Design: 
This will be a two-stage study. The study will be conducted at up to two surgical centers that 
specialize in elective abdominoplasty surgeries. The study will include a screening visit to 
determine subject eligibility. On the day of surgery, subjects will be admitted to an inpatient 
clinic for 5 days post-operatively (Days 1-5) (Table 1 and Table 2). Intraoperatively, a single 
dose of EB-001 IM will be given via IM injections into each RA 
muscles 
per 
the surgical 
procedure manual. Follow up visits will be scheduled at days 8, 
15, 
and 29. 
 
The first stage will be a 
placebo-controlled, double blinded (to subject, investigator, and site 
staff), single ascending dose cohort study. The study is stratified by ethnicity (Hispanic and 
non-Hispanic) starting from Cohort 2. Six cohorts 
(3-8 subjects per cohort) will be dosed at 6 
ascending doses of EB-001. An optional Cohort 7 may be considered. Clinical staff at the 
sponsor will be unblinded to drug assignment. 
 
 
 
 


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Cohorts 
Added 
in 
Amendment 4 (September 
2018): 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
. 
 
 
 
  
 
The second stage will be a randomized, placebo-controlled, double-blind, 
parallel 3-arm 
study (Sponsor will also be blinded). In this stage, 
there will be 2 doses of EB-001 (to be 
determined by the SRC after 
last dosing of last subject of Stage 1) and placebo in a 
1:1:1 
ratio for a total of 66 subjects stratified by ethnicity (Hispanic and non-Hispanic). SRC will 
meet periodically to review safety 
data. 
 
 
 
 
 
 


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Investigational 
(Study) 
Sites: 
It  is  expected  that  up  to  2  clinical  surgical  sites  will  conduct  the  study  and  enroll 
approximately 
90-98 
subjects. 
Duration: 
The expected study duration for each subject includes up to 45 days in screening, and 
approximately 4 weeks from the day of surgery to the last visit, for a total duration of up to 
approximately 10 weeks from the signing the Informed Consent Form (ICF) to the last study 
visit. 
 
Inclusion 
Criteria: 
An individual must meet ALL the following criteria to participate in this study: 
 
1. Men or women 23 
to 55 
years of age, inclusive 
2. Men or women who are in good health as determined by medical history, physical 
examination, clinical laboratory 
studies, ECGs, vital signs, and Investigator judgment 
3. Scheduled to undergo elective abdominoplasty surgery with  full  length  plication 
from  xyphoid  to  pubis,  and  removal  of  skin/fat  flap  under  general  anesthesia 


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(endotracheal or 
otherwise) without liposuction 
4. American Society 
of Anesthesiologist (ASA) 
Physical Class 1-2 
5. Women of non-childbearing potential or postmenopausal (at least 12 consecutive 
months of amenorrhea) 
6. Women of childbearing potential must not be pregnant, lactating, or planning to 
become pregnant during the study 
7. Women of childbearing 
potential agreeing 
to use 
either: 
a. a highly effective method of contraception with failures rates less than 1% per 
year such as implant, intrauterine device (IUD), or confirmed sterilization and 
sterilization procedure at least 3 months prior to the day of dosing 
b. dual methods of contraception with overall failures rate less than 1% per year 
such as injectable, pill, patch, ring, and diaphragm from the day of dosing for  3 
months (subjects using oral contraception must have initiated treatment at least 
2 months prior to the day of dosing) 
8. Men with partner(s) of childbearing potential agreeing to use dual methods of 
contraception from the day of dosing until  3 months afterwards, and to no sperm 
donation from 
day of dosing until 3 months afterwards. 
9. Willing and able to complete protocol requirements and instructions, which includes 
completion of all required visits, procedures and in-clinic stays until the end of the 
study 
10. Willing and able to sign and date IRB-approved informed consent 
11. Able to speak, read, and understand the language of the informed consent form 
(ICF) and study 
questionnaires 
 
Exclusion 
Criteria: 
An individual who meets ANY of 
the following criteria will be excluded from participation in 
this study: 
 
1. History of prior major abdominal surgery as judged by the investigator 
2. Pre-existing  lung disease  that  could  impact  subject  safety  in  the  opinion  of  the 
investigator 
3. History of smoking within the past two years 
4. Pre-existing  disorders  of  the  neuromuscular  junction  (myasthenia  gravis,  Eaton- 
Lambert 
syndrome, 
or amyotrophic lateral Sclerosis) 
5. Any past or current medical condition that in opinion of investigator, puts subject at 
undue safety risk for surgical complications or for 
use of the investigational product 
6. Unacceptable risk 
of deep vein 
thrombosis (DVT) 
as deemed 
by 
the investigator 
7. Past major surgery (more than 45 minutes) within the last 6 months 
8. History of blood clots, either DVT or 
pulmonary embolism 
9. Current or pst malignancies (excluding skin cancer, but not melanoma) within the last 
12 months 
10. History of diabetes 
11. Any clinically significant psychiatric condition that, in opinion of investigator, may 
interfere with study 
assessments 
or 
protocol compliance 


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12. History of alcohol or drug abuse in the last 3 years, based on investigator judgement 
13. Slow vital capacity that is below 80% 
of normal value for respective race, age, height, 
and gender or below 2.5 L of absolute volume 
14. Pulse 
oximetry below 
95% 
15. Body weight less than 50 kg (110 pounds) or a Body Mass Index (BMI) of ≥ 32 
16. Documented diagnosis of chronic pain condition, or other painful pre-operative 
condition that, in the opinion of the investigator, may require analgesic treatment in 
the post-operative period (e.g. significant joint pain, neuropathic 
pain) 
17. Known hypersensitivity to any botulinum toxin serotype or to any component of the 
formulation 
18. Reported use of any 
botulinum toxin within 3 months prior 
to the date of surgery 
19. Anticipated use of any botulinum toxin of any serotype during the study 
20. Use of long acting opioids within  3 days or any opioid medication within 24 hours 
prior to surgery 
21. Aminoglycoside intake within 48 hours 
prior to or 
during surgery 
22. Use of anti-depressant or anti-psychotic medications in the past 3 months 
23. Current enrollment in an investigational drug or device study or participation in such 
a study within 30 days or 5 half-lives of the drug, whichever is longer, of entry into 
this study 
24. Subject plans to donate blood or plasma from 30 days prior to screening until last 
follow-up visit (Day 
29) 
25. Reported  pain  score  of  2  or  more  at  screening  on  the  11-point  scale  NPRS-A 
following an activity after and walking approximately 10 
feet. 
Dosage: 
The total dose of active drug will be the specified amount of EB-001 
. Each dose will be administered into the RA muscles per 
instructions in the surgical procedure manual. The injection paradigm will be the same for 
each cohort in Stage 1 and each arm in Stage 2. 
 
Study drug injections will be performed intraoperatively under general anesthesia, under 
direct visualization of the RA muscles. Intramuscular needle placement, types of needles 
used, and additional instructions for study drug administration are referenced in the study 
manual(s). 
 
Safety Oversight: 
The safety and tolerability data for each patient will be monitored throughout the study in a 
 


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blinded fashion by the medical monitor, investigator(s) and the SRC. In the event a patient 
experiences unacceptable safety event(s) as determined by the investigator(s) and/or the 
SRC, treatment of that subject shall be 
discontinued. 
 
The study Safety Review Committee (SRC) including the Investigators, Medical Monitor, 
Study Director as well as other ad hoc representatives as appropriate will regularly monitor 
all aspects of patient safety throughout this study. 
 
In the first stage of the study, the SRC will review all available safety data in  a blinded 
manner to assess the safety of each dose level of EB-001 prior to escalating to the next dose 
level. 
 
In the second stage of the study, the SRC will meet on  a regular ongoing basis (further 
details provided in SRC charter document) to review all available data in a blinded manner 
to assess the safety 
of EB-001. 


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Flexibility 
in Dose 
Adjustment of Stage 1: 
In the first stage of the study, if an intolerable dose is identified (based on one of the above 
5 criteria), a lower dose may be evaluated as proposed by the SRC. This lower dose may be a 
repeat of the prior lower dose cohort or an intermediary dose between the intolerable dose 
and prior lower dose cohort. If the dose is an intermediary dose, a sentinel group consisting 
of 2 subjects (1 active: 1 placebo) will be dosed first. The SRC will review all available safety 
data of the prior sentinel group through at least Day  5 post-operatively, and  6 additional 
subjects (5 active: 1 placebo) will be dosed upon 
approval. 
 
In addition, if the SRC deems appropriate, before an intolerable dose is identified, a repeat 
dose, or a dose not exceeding the planned dose of the next cohort may be evaluated. 
 
If  a repeat or lower dose (i.e., any dose at or lower than prior highest dose evaluated 
without meeting stopping criteria) is considered, subjects may be dosed without 
implementing 
sentinel 
dosing strategy. 
 
All dose escalation/adjustments or additional cohorts and corresponding sample size will be 
determined 
by the SRC. 
 
 
Screening: 
Written informed consent form (ICF), demographics and baseline characteristics, 
inclusion/exclusion criteria, medical/surgical history, height, weight and BMI, complete 
physical and focused neurological examinations, prior and concomitant medications, 12- 
lead ECG, vital signs, clinical laboratory tests (serum chemistry, lipids, hematology, 
urinalysis), immunogenicity sample collection, screens for Human Immunodeficiency Virus 
(HIV) and Hepatitis B and C, screens for alcohol and drugs of abuse, serum pregnancy test, 
strength  testing  and  pain  assessment  (NPRS-A)  following  an  activity  after  walking  for 


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approximately 10 
feet, and pulmonary 
function test (PFT; SVC, FVC and FEV1). 
Efficacy 
Assessments 
• Overall pain scores at rest using the NPRS 
o NPRS is self-assessed by the study subject for their current pain according to an 
11- point numeric pain rating scale (NPRS;  0  
- 10) where  0 equates to no pain, 
and 10 equates to the worst pain imaginable. 
o Pain assessment starts once the subject is awake and lucid from surgery at every 
2 hour timepoint (±15 minutes) until 96 hours (time of discharge). Time 0 is the 
time 
of intraoperative 
drug administration. 
o NPRS assessments scheduled between 00:00 and 06:00 may be skipped if the 
subject is sleeping except for the 12 hour pain assessment if it falls between 
00:00 
and 
06:00. 
o On the mornings (10:00 ±4 hours) of Days  6-29 (inclusive), subjects will be 
encouraged to record their worst pain at rest since the last assessment of their 
pain intensity in their 
take home Pain Assessment 
Diary. 
• Pain assessment using 
NPRS-A 
o After completing the overall pain assessment at rest, the investigator will ask the 
subjects to sit up in the bed unassisted at an angle of approximately 45 degrees 
or more, swing legs out, put feet down, stand up, and walk for approximately 10 
feet. Subjects will then be asked to rate their level of worst pain when 
performing the activities using the NPRS-A. Pain assessments for NPRS-A will be 
conducted every 
8 hours 
on Day 1, and every 6 hours on Day 2 and after. 
o NPRS-A assessments scheduled between 00:00 and 06:00 may be skipped if the 
subject is sleeping except for the 12-hour pain assessment if it falls between 
00:00 
and 06:00. 
o At visits on Days 8, 15, and 29, 
the NPRS-A assessment will be performed. 
• PGA of pain control 
o Each subject will be asked the following question: Overall, please rate how well 
your pain has been controlled during the last 24 hours? Poor (0), Fair (1), Good 
(2), or Excellent (3). 
• Use of 
rescue 
medications over 
the 
post-surgical 
assessment periods 


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• In the event rescue medication is used, pain assessments using NPRS and NPRS-A 
will be recorded immediately 
prior to administering rescue medication. 
 
General 
Statistical 
Considerations: 
The final analysis will be performed when all patients have completed Day 29 visit or exited 
early from the study. The statistical analysis plan detailing all analyses will be signed off 
before the final 
database lock. 
 
Study Populations 
For efficacy analysis, modified intent to treat (mITT) population will include all randomized 
and treated patients with at least one post-injection pain score. All efficacy analyses will be 
performed using this population. Analyses will be performed on subjects using their 
randomized 
treatment 
group. 
 
The Per Protocol (PP) population will include all subjects in the mITT population with no 
major protocol violations. The primary efficacy variable will also be analyzed using this 
population. 
 
The Safety population will include all subjects exposed to any amount of study drug. All 
safety analyses will be performed using 
the safety population. 
 
Sample Size 
Subjects will be allocated to receive either EB-001 or placebo in a 1:1 ratio in Cohorts 1-3, a 
4:1 ratio in Cohort 4,  a 2:1 ratio in Cohort 5,  a 3:1 Ratio in Cohort 6, and  a 5:1 ratio in 
Optional Cohort 7 in Stage 1 stratified by ethnicity (Hispanic and non-Hispanic) starting from 
Cohort 2. The planned total sample size in Stage 1 will be up to 40-58 subjects (up to 24-39 
for EB-001 and up to 16-19 for 
placebo) (Figure 1). 


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Subjects in each arm of Stage  2 will be randomly allocated to receive either EB-001 or 
placebo. The planned total sample size will be 66 subjects (44 for EB-001 and 22 for placebo) 
in Stage 2 stratified 
by ethnicity (Hispanic and non-Hispanic) (Figure 1). 
 
Sample size of this study is not based on formal computations. However, 22 for active and 22 
for placebo provide ~67% power to detect the difference. This power is based on one-sided 
alpha of 0.05,  a mean baseline maximum pain score of 7.5, AUC12-96 ~440 with no drug 
effect, the delta AUC of 110 (drug and placebo difference), and SD 
of 170 AUC12-96. 
 
Demographic and 
baseline characteristics will be 
summarized. 
 
Safety will be assessed by summarizing the incidence of all adverse events, TEAEs, and 
serious adverse events in the Safety population. Other safety parameters (clinical laboratory 
parameters, vital signs, ECG measures, and pulmonary functions), including mean absolute 
change 
from 
baseline, 
will be summarized by 
treatment group. 
 
The primary efficacy variable is the Area under the Curve (AUC) of subject’s NPRS 
assessment between 12 and 96 hours post-surgery (AUC12-96). The primary efficacy 
variable will be summarized by treatment group. The Secondary Efficacy Measures include 
AUC assessment of overall pain profile using NPRS for various time duration. Secondary 
efficacy variables also include: NPRS at Days  6 through 29, NPRS-A over the first 96 hours 
and at Days 8, 15, 29, patient global assessment (PGA) of pain control, and use of rescue 
medications over various postsurgical periods. The statistical analyses for primary and 
secondary variables will be outlined in detail in the final SAP
. 
 
While this is not a formally powered study for efficacy analyses, efficacy data from the study 
will allow assessment of efficacy signal or trends, and exploration of the efficacious dose 
range. This will allow dose selection for 
future studies. 


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If a subject requests rescue medication, the pre-rescue pain NPRS and NPRS-A assessments 
will be carried forward for  4 hours. Handling of missing data for subjects who discontinue 
the study will be specified in the SAP
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2.1.4 Nonclinical Evaluation of EB-001 
EB-001 has been evaluated in a series of pharmacology and non-clinical toxicology studies 
 
 
 
 
 
 
  


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2.2 Rationale 
2.2.1 Study Rationale 
BoNT serotype E (BoNT/E) has been previously studied in human subjects with injection into 
the extensor digitorium brevis foot muscle (Eleopra et al. 1998; Eleopra et al. 2002). These 
studies suggested a distinct clinical profile for BoNT/E versus the BoNT/A toxins, with faster 
onset and more limited duration of effect. IM administration of EB-001 bilaterally into 
pectoralis muscles during surgery has the potential to decrease post-operative focal 
musculoskeletal pain in the chest, including muscle spasm, pain and sensation of tightness. 
The efficacy is expected to start early in post-surgical period and is expected to last 
approximately 2-4 
weeks. 
Musculoskeletal pain is defined as pain originating from the skeletal muscles, tendons or 
ligaments due to focal injury in these structures. In subjects undergoing mammoplasty with 
sub-pectoral implant placement, the pectoralis major muscle is manipulated in order to 
form  a sub-pectoral pocket for placement of the implant. Similarly, the RA muscle is 
stretched during plication in abdominoplasty. This manipulation of the RA muscles results in 
localized pain, muscular spasm, tenderness, and upper chest tightness or heaviness. 
Intramuscular injection of EB-001 is thought to reduce pain by relaxing the injured muscle, 
and by decreasing tension on the RA muscles and its tendons. 


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Table 3 
Likely Symptoms of Botulinum Toxin Poisoning or 
Overdose 
 
Body and Limbs Category 
• Decreased 
muscle tone 
• Muscle weakness 
of all four limbs 
• Loss of muscle function 
• Partial 
loss 
of voluntary 
movement 
• Loss of muscle 
tone 
• Partial 
paralysis of one limb 
• Weakened 
reflexes 
• Partial 
paralysis of one side of the 
• Lack 
of reflexes 
body 
• Muscular 
weakness 
• Partial paralysis of the lower limbs 
 
• Pelvis muscle 
weakness 
Brain 
Category 
• Inability 
to send signals from your 
brain to your body 
• Interruption between brain and 
nerves in muscle 
Eyes Category 
• Abnormal 
pupil reflex 
• Partial 
loss 
of eye movement 
• Blurred 
vision 
• Partial loss of eye muscle movement 
• Double vision 
(eyelid) 
• Drooping of upper eyelid 
• Partial loss of eye muscle movement 
• Eyelid function irregularity 
(vertical 
glaze) 
• Inability 
to focus or maintain a clear 
 
image 
 
Face Category 
• Loss of facial movement 
• Loss of movement in face 
• Loss of feeling in face 
• Partial loss 
of feeling in face 
Heart and Lungs 
Category 
• Difficulty 
breathing 
• Slowed 
breathing 
• Inflammation of the lungs 
• Slow heart 
rate 
• Shortness of 
breath 
 
Mouth 
Category 
• Difficulty speaking 
• Partial loss 
of facial motor functions 
• Difficulty 
swallowing 
(biting 
and chewing) 
• Difficulty with motor skills (slurred 
• Partial 
loss 
of tongue movement 
speech, 
difficulty chewing and 
• Speech 
impediment 
swallowing) 
• Stuttering 
• Dry mouth 
• Weakness of vocal cords 
• Inability 
to move vocal cords 
 
Stomach and 
Intestine Category 
• Bowel 
blockage 
• Unable 
to urinate completely 
• Constipation 
 


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The safety evaluations in this protocol related to potential spread of toxin were based on the 
extensive knowledge about the systemic manifestations of botulism. It is well established 
that hematogenous spread of botulinum toxin leads to classic descending flaccid paralysis 
that starts with cranial nerve manifestations  (Sobel, 2005, Gaware, 2011) followed by 
symmetrical descending flaccid paralysis that may progress to respiratory compromise 
(Sobel, 2005). The earliest symptoms of botulism are typically diplopia and ptosis followed 
by facial or pharyngeal muscle paralysis progressing to upper and then lower extremity 
weakness, and finally appearance of respiratory symptoms due to diaphragm weakness. This 
classic progression of symptoms  and signs suggests that SOT effects in the face would 
manifest before extremity weakness and respiratory symptoms. This is the basis for the 
focused neurological exam aimed at detecting SOT. In the event of systemic toxicity with EB- 
001, the muscle paralytic effect  is expected  to begin  recovering approximately  1 week 
following dosing. In contrast, the muscle paralytic effect of Botulinum Tox
in Type  A is long, 
lasting up to several weeks to months. 
 
Another risk is the possibility of an allergic reactions to drugs and to product ingredients. If a 
subject has a severe allergic reaction, death could occur. Likely signs or symptoms of allergic 
reactions (anaphylaxis) that could be life-threatening are: 
 
• Rash 
• Difficulty in breathing or inability to breathe without assistance 
• Wheezing 
• Sudden drop in blood pressure (dizziness) 
• Swelling around 
the mouth, throat, or eyes 
• Fast pulse 
• Sweating 
• Feeling of dread 
 
Documented events of serious allergic reactions have been rare in the case of botulinum 
neurotoxin serotype A (for example, see Botox® Cosmetic Label). 
 
Localized pain, infection, inflammation, tenderness, swelling, erythema, and/or 
bleeding/bruising may be associated with the injection. 
 
2.3.2    Known Potential Benefits 
Potential benefits to subjects in this study may be decreased pain following abdominoplasty 
and a decrease in the use of opioid medications 
post-surgery. 
 
3 OBJECTIVES AND PURPOSE 
This study will evaluate the safety and efficacy of EB-001 in decreasing the post-surgical pain 
in patients 
undergoing elective abdominoplasty 
surgery. 
 
The safety objective is to determine the safety and tolerability of  a single intraoperative 


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treatment of EB-001 IM injections into the RA muscles in subjects undergoing elective 
abdominoplasty 
surgery. 
 
The efficacy objective is to evaluate the efficacy of intraoperative administration of EB-001 
IM into the RA muscles in reducing the pain and use of rescue pain medications in subjects 
undergoing 
elective abdominoplasty surgery. 
 
4 STUDY DESIGN AND ENDPOINTS 
4.1 Description of the Study Design 
This will be a two-stage study. The study will be conducted at up to two surgical centers that 
specialize in elective abdominoplasty surgeries and enroll up to 39-57 subjects in Stage  1 
and 66 subjects in Stage 2 (Figure 1), with up to 67-82 subjects exposed to active drug. The 
study will include  a screening visit to determine subject eligibility. On the day of surgery, 
subjects will be admitted to an inpatient clinic for 5 days post-operatively (Days 1-5) (Table 1 
and Table 2). Intraoperatively, a single dose of EB-001 IM will be given via IM injections into 
the RA muscles per the surgical procedure manual. Follow up visits will be scheduled at days 
8, 15, and 29. 
 
The first stage will be a placebo controlled, single-blind (to subject and staff at study sites), 
single ascending cohort study stratified by ethnicity (Hispanic and non-Hispanic) starting 
from Cohort 2. Six cohorts (3-8 subjects per cohort) will be dosed at  6 ascending doses of 
EB-001. An optional Cohort 7 may 
be considered. 
 
Cohort 1 sentinel group (3 subjects; 1 active: 2 placebo) 
 The rest 
of the cohort (5 subjects; 3 active: 2 placebo) will be dosed at the same dose after review of 
all available data by the Safety Review Committee (SRC) is conducted, with safety data 
through at 
least 
Day 5 
post-operatively. 
 
Cohort 2 sentinel group (3 subjects; 1 active: 2 placebo) 
 after 
review of all available safety data from the prior cohort through at least Day  5 post- 
operatively. The rest of the cohort (5 subjects;  3 active:  2 placebo) will be dosed after 
review of all available data by the SRC is conducted, with safety data through at least Day 5 
post-operatively. 
 
Cohort 3 sentinel group (3 subjects; 1 active: 2 placebo) 
 after 
review of all available safety data from the prior cohorts through at least Day  5 post- 
operatively. The rest of the cohort (5 subjects;  3 active:  2 placebo) will be dosed after 
review of all available data by the SRC is conducted, with safety data through at least Day 5 
post-operatively. 
 
Cohort  4 group (5 subjects;  4 active:  1 placebo) 
 after review of all 
available safety data 
from the prior cohort 
through at least Day 5 post-operatively. 


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Cohort  5 group (3 subjects;  2 active:  1 placebo) 
 after review of all 
available safety data 
from the prior cohort 
through at 
least Day 5 post-operatively. 
 
Cohort  6 sentinel group (2 subjects;  1 active:  1 placebo) 
 after 
review of all available safety data from the prior cohorts through at least Day  5 post- 
operatively. The rest of the cohort (6 subjects;  5 active:  1 placebo) will be dosed after 
review of all available data by the SRC is conducted, with safety data through at least Day 5 
post-operatively. 
 
Optional Cohort 7 (up to 18 subjects; 15 active: 3 placebo) will be dosed at a dose previously 
assessed after review of all available safety data from the prior cohorts through at least Day 
5 post-operatively. 
 
In the event an intolerable dose is identified, a lower (intermediary) dose may be evaluated 
as proposed by the SRC. This lower dose may be a repeat of the prior lower dose cohort or 
an intermediary dose between the intolerable dose and prior lower dose cohort. See further 
details in Flexibility in Dose Adjustment of Stage 1. 
 
The second stage will be a randomized, placebo-controlled, 
double blind, 
parallel 3-arm 
study. In this stage, there will be 2 doses of EB-001 (to be determined by 
the SRC after last 
dosing of last subject of Stage 1) and placebo in a 1:1:1 ratio for a total of 66 subjects 
stratified by ethnicity (Hispanic and non-Hispanic). SRC will meet periodically to review 
safety data. 
 
Investigational 
(Study) 
Sites: 
It is expected that up to  2 clinical surgical sites will conduct the study and enroll 
approximately 
105-123 
subjects. 
 
 
 
 
  
 
Placebo: 
 
 
Dosage: 
The total dose of active drug will be the specified amount of EB-001 
 
. Each dose will be administered into the RA muscles per 
instructions in the surgical procedure manual. The injection paradigm will be the same for 
each cohort. 
 
Study drug injections will be performed intraoperatively under general anesthesia, under 
direct visualization of the RA muscles. Intramuscular needle placement, types of needles 
used, and additional instructions for study drug administration are referenced in the study 
 


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manual(s). 


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Table 4  
Toxicity Criteria 
TEAE 
Definition1 
 
Serious 
adverse 
event 
See 
Section 8.1.2 
TEAEs related  to  spread  of  toxin,  including 
PFTs 
SOT:    FDA    Draft    Guidance:    Upper    Facial    Lines: 
Developing 
Botulinum Toxin 
Drug 
Products2 ≥Grade 2 
SVC: SVC on PFT with a reduction of greater than 40% 
relative to baseline pre-dose measure and the absolute 
SVC less than 2 L at 96 hours (Day 5) post-dose or later, 
when  confirmed  by  a  repeat  SVC  approximately   4 
hours 
later. 
Post-operative 
TEAEs 
of 
Special 
Interest 
Tachypnea,  tachycardia,  and  fever  according  to  the 
Guidance  for  Vaccine  Trials  in  Healthy  Volunteers3 
≥Grade 2 
Pneumonia   or   atelectasis   diagnosed   clinically   and 
confirmed 
by chest x-ray 
Dyspnea with a clinical diagnosis of moderate or worse 
severity 
TEAEs related to Laboratory and ECG 
parameters4 
All others TEAEs (other than the SOT, post- 
operative TEAEs of Special Interest, or 
laboratory 
and 
ECG 
parameters) 
Guidance  for  Vaccine  Trials  in  Healthy  Volunteers3 
≥Grade 2 
Guidance  for  Vaccine  Trials  in  Healthy  Volunteers3 
≥Grade 3 
1  Unless 
considered to be 
unrelated to study medication 
2  FDA Draft Guidance, Upper 
Facial Lines: 
Developing 
Botulinum 
Toxin Drug 
Products (FDA 2014). 
3  Guidance for Industry: Toxicity Grading Scale for Health Adult and Adolescent Volunteers Enrolled in 
Preventive 
Vaccine 
Clinical Trials (FDA 
2007) 
4  To be confirmed by a repeat test 
 
Flexibility 
in Dose 
Adjustment of Stage 1: 
In the first stage of the study, if an intolerable dose is identified (based on one of the above 
5 criteria), a lower dose may be evaluated as proposed by the SRC. This lower dose may be a 
repeat of the prior lower dose cohort or an intermediary dose between the intolerable dose 
and prior lower dose cohort. If the dose is an intermediary dose, a sentinel group consisting 
of 2 subjects (1 active: 1 placebo) will be dosed first. The SRC will review all available safety 


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data of the prior sentinel group through at least Day  5 post-operatively, and  6 additional 
subjects (5 active: 1 placebo) will be dosed upon 
approval. 
 
In addition, if the SRC deems appropriate, before an intolerable dose is identified, a repeat 
dose, or a dose not exceeding 
the planned dose of the next cohort may be evaluated. 
 
If  a repeat or lower dose (i.e., any dose at or lower than prior highest dose evaluated 
without meeting stopping criteria) is considered, subjects may be dosed without 
implementing sentinel 
dosing strategy. 
 
All dose escalation/adjustments or additional cohorts and corresponding sample size will be 
determined 
by the SRC. 
 
4.2 Study Endpoints 
4.2.2 Primary Efficacy Endpoint 
• Area under the curve (AUC) of subject’s assessment of pain using the Numeric Pain 
Rating Scale (NPRS) between 
12 and 
96 
hours post-surgery (AUC
12-96). 


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4.2.3 Secondary Efficacy Endpoints 
• AUC assessment of overall pain profile using NPRS: 
o Over the first 96 hours post-surgery (AUC
0-96)  
o Over the first 72 hours post-surgery (AUC
0-72)  
o Over the first 48 hours post-surgery (AUC
0-48)  
o Over the first 24 hours post-surgery (AUC
0-24) 
o Over the period of 12 to 
24 hours post-surgery (AUC
12-24) 
o Over the period of time  X to 96 hours post-surgery (AUC
t-96), whereas  X is any 
time 
during confinement 
• Pain assessment at rest after discharge using 
NPRS at Days 6 through 
29. 
• Pain assessment after sitting up in the bed unassisted at an angle of approximately 
45 degrees or more, swinging legs out, putting feet down, standing up, and walking 
approximately 10 feet using NPRS-A (NPRS administered after an activity) over the 
first 96 hours and at Days 8, 15, 29. 
• Patient global assessment (PGA) of pain control 
• Use of 
rescue 
medications over various 
postsurgical periods 
 
5 STUDY ENROLLMENT AND WITHDRAWAL 
Prior to shipment of study drug and before subjects may be enrolled in the study, the 
Sponsor or designee requires a copy of the following critical 
documents: 
 
• Institutional Review Board (IRB)  / Independent Ethics Committee (IEC) approval of 
the 
protocol and the subject Information Sheet / Informed Consent Form (ICF); 
• Signed and dated protocol signature 
page; 
• Completed Food and Drug Administration (FDA) Form 1572 (central laboratories and 
any local laboratories for the study must be listed 
on the form); 
• Up-to-date  curricula  vitae  and  medical  licenses  (if  applicable)  of  the  Principal 
Investigator (PI) and all Sub-Investigators listed on the FDA 
Form 
1572; 
• Signed  financial  disclosure  forms  for  the  Principal  Investigator  (PI)  and  all  Sub- 
Investigators listed on 
the FDA Form 
1572; 
• Name, address, and 
membership of 
the IRB/IEC; 
• Laboratory   normal   ranges   and   documentation   of   laboratory   certification   (or 
equivalent); 
• Signed 
clinical study 
agreement; 
 
All subjects must personally sign and date an IRB-approved ICF before any study procedures, 
including screening procedures, are performed. Subjects will be considered enrolled into the 
study only when 
they have received study 
drug. 


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5.1 Participant Inclusion Criteria 
In order to be eligible to participate in this  study, an individual must meet  ALL of the 
following 
criteria: 
 
1. Men or women 23 to 55 
years of age, inclusive 
2. Men or women who are in good health as determined by medical history, physical 
examination, clinical laboratory 
studies, ECGs, vital signs, and Investigator judgment 
3. Scheduled to  undergo elective  abdominoplasty surgery with full  length plication 
from xyphoid to pubis, and removal of skin/fat flap under general anesthesia 
(endotracheal 
or 
otherwise) without liposuction 
4. American Society 
of 
Anesthesiologist (ASA) 
Physical Class 1-2 
5. Women of non-childbearing potential or postmenopausal (at least 12 consecutive 
months of amenorrhea) 
6. Women of childbearing potential must not be pregnant, lactating, or planning to 
become pregnant during the study 
7. Women of childbearing 
potential agreeing 
to use 
either: 
a. a highly effective method of contraception with failures rates less than 1% per 
year such as implant, intrauterine device (IUD), or confirmed sterilization and 
sterilization procedure at least 3 months 
prior 
to the day of dosing 
b. dual methods of contraception with overall failures rate less than 1% per year 
such as injectable, pill, patch, ring, and diaphragm from the day of dosing for  3 
months (subjects using oral contraception must have initiated treatment at least 
2 months prior to the day of dosing) 
8. Men with partner(s) of childbearing potential agreeing to use dual methods of 
contraception from the day of dosing until  3 months afterwards, and to no sperm 
donation from 
day of dosing until 3 months afterwards. 
9. Willing and able to complete protocol requirements and instructions, which includes 
completion of all required visits, procedures and in-clinic stays until the end of the 
study 
10. Willing and able to sign and date IRB-approved informed consent 
11. Able to speak, read, and understand the language of the informed consent form 
(ICF) and study 
questionnaires 
 
5.2 Participant Exclusion Criteria 
An individual who meets ANY of the following criteria will be excluded from participation in 
this study: 
 
1. History of prior major abdominal surgery as judged by the investigator 
2. Pre-existing lung disease that could impact subject safety in the opinion of the 
investigator 
3. History of smoking within the past two years 
4. Pre-existing disorders of the neuromuscular junction (myasthenia gravis, Eaton- 
Lambert 
syndrome, 
or amyotrophic lateral Sclerosis) 


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5. Any past or current medical condition that in opinion of investigator, puts subject at 
undue safety risk for surgical complications or for 
use of the investigational product 
6. Unacceptable risk of deep vein thrombosis (DVT) 
as deemed by 
the investigator 
7. Past major surgery (more than 45 minutes) within the last 6 months 
8. History of blood clots, either 
DVT or 
pulmonary embolism 
9. Current or 
pst malignancies (excluding skin cancer, but not melanoma) within the last 
12 months 
10. History of diabetes 
11. Any clinically significant psychiatric condition that, in opinion of investigator, may 
interfere with study 
assessments 
or 
protocol compliance 
12. History of alcohol or drug abuse in the last 3 years, based on investigator judgement 
13. Slow vital capacity that is below 80% 
of normal value for respective race, age, height, 
and gender or below 2.5 L of absolute volume 
14. Pulse 
oximetry below 
95% 
15. Body weight less than 50 kg (110 pounds) or a Body Mass Index (BMI) of ≥ 32 
16. Documented diagnosis of chronic pain condition, or other painful pre-operative 
condition that, in the opinion of the investigator, may require analgesic treatment in 
the post-operative period (e.g. significant joint pain, neuropathic 
pain) 
17. Known hypersensitivity to any botulinum toxin serotype or to any component of the 
formulation 
18. Reported use of any 
botulinum toxin within 3 months prior 
to the date of surgery 
19. Anticipated use of any botulinum toxin of any serotype during the study 
20. Use of long acting opioids within  3 days or any opioid medication within 24 hours 
prior to surgery 
21. Aminoglycoside intake within 48 hours prior to or 
during surgery 
22. Use of anti-depressant or anti-psychotic medications in the past 3 months 
23. Current enrollment in an investigational drug or device study or participation in such 
a study within 30 days or  5 half-lives of the drug, whichever is longer, of entry into 
this study 
24. Subject plans to donate blood or plasma from 30 days prior to screening until last 
follow-up visit (Day 
29) 
25. Reported pain score of  2 or more at screening on the 11-point scale NPRS-A after 
walking approximately 10 
feet 
 
5.3 Strategies for Recruitment and Retention 
A sufficient number of subjects will be screened to allow for approximately 90-98 eligible 
subjects 
to be randomized at up to 2 US-based investigational sites. 
 
If radio, local print advertising, or any recruitment material is considered, prior Sponsor and 
IRB approval will  be obtained. Potential  subjects will  be contacted via  telephone  for  a 
preliminary screen of some of the inclusion and exclusion criteria. Only subjects who are 
able to provide voluntary, signed written informed consent will be admitted. Preliminarily 


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eligible subjects will be invited to the clinic for complete screening, as set forth in the 
Schedule of Study Procedures. 
 
5.4 Participant Withdrawal or Termination 
5.4.1 Reasons for Withdrawal or Termination 
Participants are free to withdraw from participation in the study at any time upon request 
for any reason without prejudice to his or her future medical care by the physician or at the 
institution. A subject may be terminated 
from 
the study for any of the following reasons: 
 
• Withdrawal of informed 
consent. 
• Entry into 
the study in violation of the protocol. 
• Any AE, laboratory abnormality, or other medical condition or situation occurs such 
that the study doctor or study staff believes continued participation in the study 
would not be 
in the best 
interest of the participant. 
• The  participant  meets  an  exclusion  criterion  (either  newly  developed  or  not 
previously recognized) that precludes further study participation. 
• Noncompliance  with  the  protocol  (except  for  exceeding  limit  of  allowed  rescue 
medication; specified below in Section 5.4.3). 
• At the discretion of the Investigator or Sponsor 
for any 
reason. 
 
5.4.2 Handling of Participant Withdrawal or Termination 
If  a subject discontinues from the study prematurely, all efforts will be made to conduct 
early termination (ET) evaluations as thoroughly as possible up to the date of withdrawal at 
the 
time of discontinuation. 
 
Subjects who discontinue participation, or who are discontinued prior to completing study 
participation, will 
be asked to complete ET procedures, including: 
 
• Assessment 
of 
AEs 
• Assessment of AEs of Special Interest including post-operative dyspnea, tachypnea, 
tachycardia, 
pneumonia, 
atelectasis, and 
fever 
• Height, weight, and BMI 
• Mini-physical and focused neurological examinations 
• Prior and concomitant medications 
• 12-lead ECG 
• Body temperature, respiration rate, 
blood pressure, pulse oximetry, and 
pulse rate 
• Serum chemistry, Lipids, 
and Hematology 
• Urinalysis 
• Immunogenicity sample 
collection 
• Pregnancy 
test 
• Postoperative wound 
assessment 


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• Overall assessment of pain at rest using NPRS 
(if prior to the 96-hr assessment) 
• Pain assessment using NPRS-A after sitting up in the bed unassisted at an angle of 
approximately 45 degrees or more, swinging legs out, putting feet down, standing 
up, and walking approximately 10 feet (if prior 
to the 96-hr assessment) 
• Patient global 
assessment (PGA) of pain control 
• Pulmonary function test (SVC, FVC, and FEV1) 
• Use 
of rescue 
medications 
• Collection of 
take-home diaries (if applicable) 
 
5.4.3 Handling of Participant Exceeding Allowed Rescue Medication 
Subjects who exceed limit of allowed rescue medication, considered noncompliance with 
the protocol specified in Section 5.4.1 due to lack of efficacy, will be followed, not early 
terminated, with regard to all safety assessments per protocol. They at all subsequent visits 
will be asked to complete protocol-specified assessments, with the exception of efficacy 
assessments 
as follows: 
 
• NPRS 
• NPRS-A 
• Collection of 
take-home pain 
assessment diary 
 
5.5    Replacement of Subjects 
Up to 4 (or up to 1 subject per cohort) subjects in Stage 1 who discontinue from the study 
may be replaced (unless the discontinuation is due to one of the toxicity criteria in Section 
4.1.1 when subjects will not be replaced). Up to 9 subjects (or up to 3 subjects per cohort) in 
Stage 2 who discontinue from the study will be replaced (unless the discontinuation is due 
to safety 
reasons when subjects will not be replaced). 
 
5.6 Premature Termination or Suspension of 
Study 
This study may be temporarily suspended or prematurely terminated if there is sufficient 
reasonable cause. Written notification, documenting the reason for study suspension or 
termination, will be provided by the suspending or terminating party to Bonti. Bonti may 
also choose to suspend or terminate the study at any time for any of the reasons as noted 
below. If the study is prematurely terminated or suspended, the PI will promptly inform the 
IRB and will provide the reason(s) for the termination or suspension. 
 
Circumstances that may warrant termination 
or suspension include, 
but are not limited to: 
 
• Determination 
of unexpected, significant, 
or 
unacceptable 
risk 
to participants 
• Demonstration of efficacy that would warrant stopping 
• Insufficient compliance 
to protocol requirements 
• Data 
that are not sufficiently complete and/or evaluable 
• Determination 
of 
futility 


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Study may resume once concerns about safety, protocol compliance, and/or data quality are 
addressed and satisfy the Sponsor, IRB and/or FDA. 
6.1.5 Dosing and Administration 
See Section 
4.1. 


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6.1.6 Route of Administration 
The study drug will be administered as intramuscular (IM) injections. 
 
6.1.7 Starting Dose and Dose Escalation Schedule 
See Section 
4.1. 
 
6.1.8 Dose Adjustments/Modification/Delays in Stage 1 
If an intolerable dose is identified (based on one of the above 5 criteria), a lower dose may 
be evaluated as proposed by the SRC. This lower dose may be  a repeat of the prior lower 
dose cohort or an intermediary dose between the intolerable dose and prior lower dose 
cohort. In addition, if the SRC deems appropriate, before the intolerable dose is identified, a 
lower or  repeat dose without exceeding the dose of the next planned cohort may be 
evaluated. 
 
6.1.9 Duration of Treatment 
Expected duration is approximately  4 weeks for each subject from the day of study 
treatment to the End of Study Visit on Day 29, or up to approximately 10 weeks from signing 
ICF to the follow-up exit. 
 
6.1.10 Tracking of Study Vials and Dose 
The Investigator will keep  a record of the dates study drug vials received, the dose 
dispensed to each study subject from each vial. After dose is administered to the subject, 
the dispenser will return the vial for storage in the pharmacy until CRA conducts final drug 
accountability which will be verified and reconciled on the Study Drug Log and Study Drug 
Preparation Sheet. By the end of the study, the CRA upon conducting final drug 
accountability will instruct the dispenser or designee to ship any remaining study vials to the 
distribution center to be destroyed. Instructions for study drug preparation, dispensing and 
record keeping are referenced in 
the study 
manual(s). 
 
6.1.11 Replacement Procedures for Investigational Medicinal Product 
Instructions for resupply shipments or replacement of study drug are referenced in the 
study manual(s). 
 
6.2 Investigational Product Accountability Procedures 
It is the responsibility of the Investigator to supervise accurate monitoring of the receipt, 
storage, dose preparation, and accounting of all study drug according to accepted medical 
and pharmaceutical practice. Copies of all invoices of study drug shipments must be 
retained. Accurate, original site records of study drug inventory and dispensing must be 
maintained using 
the forms provided study manual(s). 


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All study drug documentation must be maintained by the unblinded pharmacist or 
designated unblinded personnel. All disposition records must be made available for 
inspection by Sponsor or CRO upon request. 
 
A Study Drug Log will be provided for the accounting of study drug. Study Drug Log forms 
will be provided for the accounting of study drug for each study subject and for maintaining 
the overall balance of vials.  A reason(s) must be given for any amounts that are not 
accounted for. 
 
Each site must keep all remaining study drug in the original vials until they are returned to 
the 
distribution center. 


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3). 
 
7.1.1.25 Overall Assessment of Pain at Rest Using NPRS 
Subjects will assess their overall pain level at rest since the last assessment using an 11-point 
NPRS, where 0 is no pain, and 10 is the worst pain imaginable (Appendix 4). 
 
Assessments will be made every 2 hours (±15 minutes) post-dose after the subject is awake 
and lucid from surgery, until discharge. NPRS assessments scheduled between 00:00 and 
06:00 may be skipped if the subject is sleeping. However, the 12-hour pain assessment must 
be completed even when the assessment falls between 00:00 and 06:00. Assessments will 
also be made after subjects are discharged on Days 6-29, and will be entered into the Pain 
Assessment Diary (see Section 7.1.1.31.1). 
 
In the event rescue medication is used, an assessment of pain using the NPRS prior to 
administering rescue 
medication will be recorded. 
7.1.1.26 Pain Assessment after Walking (NPRS-A) 
At baseline prior to surgery, and then every 8 hours (±15 minutes) post-dose on Day 1, and 
every  6 hours on day  2 and  after, after the subject is  awake and lucid from surgery until 
discharge, the Investigator will ask subjects to sit up in the bed unassisted at an angle of 
approximately 45 degrees or more, swing legs out, put feet down, stand up, and walk 
approximately 10 feet. Subjects will then be asked to rate their level of worst pain when 
performing the activities using the NPRS-A, on an 11-point numerical scale, where 0 means 
no pain and 10 means the worst pain imaginable (Appendix 5) while they were walking. 
 
NPRS-A assessments scheduled between 00:00 and 06:00 may be skipped if the subject is 
sleeping. However, the 12-hour pain assessment must be completed even when the 
assessment falls between 00:00 and 06:00. Assessments will also be made at each follow up 
visit on Days 8, 15, and 29. 
 
In the event rescue medication is used, an assessment of pain using the NPRS prior to 
administering rescue medication will be recorded. If subjects can not perform NPRS-A prior 
to taking rescue medication due to intolerable 
pain, this assessment may 
be omitted. 
 
7.1.1.27 Patient Global Assessment (PGA) of Pain Control 
The PGA will be evaluated at 96±2 hours (Days 5), and on Days 8, 15, and 29 (EOS/ET), using 
a  4-point categorical scale (Poor (0), Fair (1), Good (2), Excellent (3)  (Appendix  6). Each 
subject will be asked the following question: “Overall, how well your pain has been 
controlled 
during 
the last 24 hours?” (Rothman 2009) 
 


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value should be recorded in the e-CRF. The largest FVC and largest FEV1 should be selected 
and reported in the eCRF
, even if not fr
om the same spirogr
am. 
 
7.1.1.31 Take-home Diaries 
Subjects will be encouraged to maintain two take-home diaries from discharge through 
EOS/ET,
  a Pain Assessment Diary and  a Rescue Medication Diary. On Day 5, prior to 
discharge, site staff will review the diaries with subjects to ensure they understand how to 
complete them. Subjects 
will take 
the diaries 
home. 
 
At follow-up visits on Days 8, 15 and 29, subjects will return with their diaries, and site staff 
will review them for completion. Subjects will return home with both diaries at the end of 
the visit on Days  8 and 15. Both diaries will be collected by the site at the EOS/ET visit (if 
applicable). 
 
7.1.1.31.1 Pain Assessment Diary 
On the mornings of Days 6-29 (inclusive), subjects will be encouraged to record their worst 
pain at rest (NPRS) and worst pain when sitting up in the bed unassisted at an angle of 
approximately 45 degrees or more, swinging legs out, putting feet down, standing up, and 
walking approximately 10 feet (NPRS-A) since the last assessment of their pain intensity in 
their take-home 
Pain Assessment 
Diary. 
 
These scores will be captured once each in the morning (10:00 ±4 hours) using an 11-point 
NPRS and NPRS-A, where 0 is no pain, and 10 is the worst pain imaginable. Subjects will be 
encouraged to record additional pain assessment scores prior to taking rescue medication 
(Refer to Section 7.1.1.31.2). Completion of the Pain Assessment Diary will start on Day  6 
(Appendix 7). 
 
7.1.1.31.2 Rescue Medication Diary 
Subjects will be encouraged to record all rescue medication usage in their take-home Rescue 
Medication Diary. See Section 7.2 for details regarding allowable rescue medication. 
Subjects will be instructed to complete an entry in their Pain Assessment Diary prior to 
taking rescue medication. Completion of the Rescue Medication Diary will start immediately 
following discharge on Day 5. In the event rescue medication is taken by the subject 
following discharge on Day 5, subjects will be encouraged to record their pain scores prior to 
taking the rescue medication  
(Appendix  8). In the event subjects can not perform NPRS-A 
due to intolerable pain, this assessment may be omitted. 
 


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7.3 Laboratory Procedures/Evaluations 
7.3.1 Clinical Laboratory Evaluations 
See Sections 7.1.1.14, 7.1.1.15, 7.1.1.16, 7.1.1.17, 7.1.1.18, and 7.1.1.19. 
 
7.3.2 Specimen Preparation, Handling, and Storage 
See Laboratory Manual for instructions of specimen preparation, handling, and storage. 
 
7.3.3 Specimen Shipment 
See Laboratory Manual for instruction of specimen shipment. 


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7.3.4 Volume of Blood Collected 
The estimated total blood volume collected throughout the study for clinical laboratory and 
immunogenicity tests is summarized in Table
 5 and is expected to 
be approximately 72 mL. 
 
Table 5  
Total Blood Volume Collected for 
Each Patient 
 
 
Test 
Blood 
Sample 
Volume 
Number 
of 
Tests 
Total 
Volume 
Hematology1 
4 mL 
4 
16 mL 
Serum 
chemistry
1, Lipids, 
Serum 
pregnancy 
test
2 
8.5 mL 
4 
34 mL 
HIV 
1/O/2 
5 mL 
1 
5 mL 
HBsAG 
and HCV Ab 
5 mL 
1 
5 mL 
Serum 
samples 
for 
immunogenicity 
4 mL 
3 
12 mL 
 
TOTAL 
72 mL 
1 Additional 
blood may be 
collected for safety laboratory tests, if 
clinically indicated 
2 Female 
of 
child bearing potential 
only 


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7.6 Prohibited Medications, Treatments, and Procedures 
During  the  study,  subjects  may  not  use  the  following  medications,  or  have  following 
treatments/procedures 
performed in 
postoperative period 
throughout the 
EOS Visit. 
 
• Any analgesics other than those specified in Section 7.5 
• Use of botulinum neurotoxin treatment of any serotype 
• Use of aminoglycosides 
• Use of skeletal muscle relaxants 
• Antiemetic’s may 
be used to treat nausea, 
but may not 
be 
used prophylactically 
• Ice may not be used as a non-medication therapy 
 
7.7 Subject Restrictions 
The following 
restrictions apply: 
 
• Women of childbearing potential must 
agree to 
use either 
o a highly effective method of contraception with failures rates less than 1% per 
year such as implant, IUD, or sterilization from the day of dosing for  3 months 
(subjects who underwent sterilization must have initiated the procedure at least 
3 months prior to the day of dosing) or 
o dual methods of contraception with overall failures rates less than 1% per year 
such as injectable, pill, patch, ring, and diaphragm from the day of dosing for 
3 months (subjects using oral contraception must have initiated treatment at 
least 2 months prior to the day of dosing). 
• Men with partner(s) of childbearing potential agreeing to use dual methods of 
contraception from the day of dosing until  3 months afterwards, and to no sperm 
donation from 
day of dosing until 3 months afterwards. 
• Subjects must not donate blood or plasma from 30 days prior to Screening until the 
last follow-up visit (Day 29). 


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8.1.1 Definition of Adverse Events (AE) 
Information about adverse events including those of Special Interest, whether reported by 
the subject, discovered by the Investigator by questioning/review of diary records or 
detected through physical examination, laboratory test or other means, will be collected and 
recorded on the adverse event form and followed-up as appropriate. Information about 
serious adverse events must be reported within 24 hours of obtaining knowledge of the 
event. 
 
An adverse event (AE), defined according to International Committee on Harmonisation 
(ICH) Harmonized Tripartite Guideline E2A, is any untoward medical occurrence in a subject 
or clinical trial subject administered  a trial product and which does not necessarily have  a 
causal relationship with this treatment. An AE can therefore be any unfavorable and 
unintended sign (including  a laboratory finding, for example), symptom, syndrome, or 
disease temporally associated with the use of  a medicinal product, whether or not 
considered related to the medicinal product. Post-operative dyspnea, tachypnea, 
tachycardia, pneumonia, atelectasis, and fever are AEs of Special Interest, and will be closely 
monitored. Other examples of AEs include: 
 
• Any treatment-emergent signs and symptoms [events that are marked by  a change 
from the subject’s baseline/entry status (e.g., an increase in severity or frequency of 
pre-existing abnormality 
or disorder)] 
• All reactions from study drug, abuse of drug, withdrawal phenomena, sensitivity, or 
toxicity to study drug 
• Apparently 
unrelated illnesses 
• Injury or accidents 
• Exacerbations of 
the 
underlying disease (indication) 
• Extensions or exacerbations or symptomatology, subjective events reported by the 
subject, new clinically significant abnormalities in clinical laboratory, physiological 
testing, or physical examination 
 
The following is not considered an AE: 
 
• Pre-planned procedure (documented as concomitant illness on the CRF at screening) 
unless the condition for which the procedure was planned has worsened from the 
first trial related activity 
after the subject has 
signed the informed consent 
form. 
• Pre-existing conditions found as a result of screening 
procedures. 
 
8.1.2 Definition of Serious Adverse Events (SAE) 
In addition to the severity rating, each AE is to be classified by the Investigator as “serious” 
or  “not serious.”  The  seriousness  of  an  event  is  defined  according  to  the  applicable 


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regulations and generally refers to the outcome of an event. A serious adverse event (SAE) is 
one that meets one or more of the following: 
• Is fatal 
• Is 
immediately 
life-threatening 
• Is permanently (or significantly) disabling 
• Requires 
hospitalization 
• Prolongs existing hospitalization 
• Is a congenital anomaly 
or birth defect (in an offspring) 
• Is judged medically significant 
 
Definition 
of 
Life-threatening 
 
A life-threatening event places the subject, in the view of the Investigator, at immediate risk 
of death from the event as it occurred. This does not include an adverse event, which, had it 
occurred in a more severe form, might have caused death. 
 
Definition 
of 
Hospitalization 
 
Hospitalization is defined by the Sponsor as a full admission to the hospital for diagnosis and 
treatment. This includes prolongation of an existing inpatient hospitalization. 
 
Examples  of  visits  to  a  hospital  facility  that  do  not  meet  the  serious  criteria  for 
hospitalization include: 
 
• Emergency room visits (that do not result in a full hospital admission) 
• Outpatient surgery 
• Preplanned or elective 
procedures (See 
Section 8.1.2.1) 
• Protocol 
procedures 
 
These events would not be reported as SAEs unless: 
 
• The event triggering the hospital visit is an SAE as defined by other SAE criteria such 
as life-threatening, results in persistent or significant disability/incapacity or as per 
medical judgement of Investigator 
• Any other event fulfilling the definition of serious that develops as a result of the in- 
hospital procedure or extends the hospital stay is 
an SAE 
 
Definition 
of 
Disability 
 
Disability is defined as  a substantial disruption in  a person’s ability to conduct normal life 
functions. 
 
Definition 
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Important medical events (medically significant events) that may not result in death, be life- 
threatening or require hospitalization may be considered to be an SAE when, based upon 
appropriate medical judgement, they may jeopardize the subject or may require medical or 
surgical intervention to prevent one of the outcomes listed in this definition. 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. 
 
An SAE may also include any other event that the Investigator, or Medical Monitor or 
designee judges to be serious, or that suggests  a significant hazard, contraindication, side 
effect, or precaution. 
 
8.1.2.1    Elective Procedures, and Surgeries 
For the purposes of this Protocol, the following conventions will apply for SAE reporting of 
elective 
procedures, 
and 
surgeries: 
 
A pre-scheduled elective procedure or  a routinely scheduled treatment is not to be 
considered an SAE, 
even if the 
subject is 
hospitalized, 
provided the site stipulates that: 
 
• The condition requiring the pre-scheduled elective procedure or routinely scheduled 
treatment was present before and did not worsen or progress between the subject’s 
consent to participate in the clinical  trial and the time of the procedure or 
treatment. 
• The pre-scheduled elective procedure or routinely scheduled treatment is the sole 
reason for 
admission and intervention. 
 
An untoward medical event occurring during the pre-scheduled elective procedure or 
routinely scheduled treatment must be recorded as an AE or  a SAE. Record any concurrent 
medications on the eCR
F. 
 
8.1.3 Definition of Unanticipated Problems (UP) 
The Office of Human Research Protection (OHRP) considers unanticipated problems 
involving risks to participants or others to include, in general, any incident, experience, or 
outcome that 
meets all of the 
following criteria: 
 
• Unexpected in terms of nature, severity, or frequency given (a) the research 
procedures that are described in the protocol-related documents, such as the IRB- 
approved research protocol and informed consent document; and (b) the 
characteristics 
of the 
participant 
population 
being 
studied 
• Related to participation in the research 
• Research placing participants or others at a greater risk of harm (including physical, 
psychological, economic, or social harm) 
than was 
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This study will use the OHRP definition of UP.
 
 
8.2 Classification of an Adverse Event 
8.2.1 Severity of Event 
AEs will be assessed according to the Guidance for Industry: Toxicity Grading Scale for 
Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials (FDA 
2007). Adverse events including those of Special Interest that do not have a corresponding 
term in the Guidance may be considered a systemic illness (Illness or clinical adverse event 
(as defined according to applicable regulations)), and will be assessed according to their 
impact on the participant’s ability to perform 
daily activities as listed below: 
 
• Mild (Grade 1): No interference with activity 
• Moderate   (Grade   2):  Some   interference   with   activity   not   requiring   medical 
intervention 
• Severe (Grade 3): 
Prevents daily 
activity and 
requires medical intervention 
• Potentially Life threatening (Grade 4): ER visit or 
hospitalization 
 
These four  categories are based on the Investigator’s clinical judgement, which in turn 
depends on consideration of various factors such as the subject’s reports, the physician’s 
observations, and the physician’s prior experience. Record the severity of the AE in the 
appropriate section of the AE page of the  eCR
F. The evaluation of severity is distinguished 
from the evaluation of “seriousness” (see Section 8.1.2). A severe event might not meet the 
criteria for seriousness and  a serious event might be evaluated as mild. For example,  a 
subject might have  a severe headache that does not require hospitalization and is 
consequently not serious; or a subject might have a mild myocardial infarction that requires 
hospitalization and is therefore serious. 
 
8.2.2 Relationship to Study Agent 
The causality of each adverse event must be assessed and classified by the Investigator as 
“related” or “unrelated”
. An event is consider
ed r
elated if there is “a reasonable possibility” 
that the event may have been caused by the product under investigation (i.e., there are 
facts, evidence, or arguments 
to suggest possible causation). 
 
Categories of attribution 
for “Related” events: 
• Definitely related: There is clear evidence to suggest a causal relationship, and other 
possible contributing factors can be ruled out. 
• Probably  related:  There  is  evidence  to  suggest  a  causal  relationship,  and  the 
influence of other 
factors is unlikely. 
• Possibly related: There is some evidence to suggest  a causal relationship (e.g., the 
event occurred within  a reasonable time after administration of the study drug). 
However, the influence of other factors may have contributed to the event (e.g., the 
subject’s 
clinical condition, other 
concomitant 
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Categories of attribution 
for “Unrelated” 
events: 
• Unlikely related: There is little evidence to suggest there is  a causal relationship. 
There is another reasonable explanation 
for the event. 
• Not related: An AE will be considered “not related” to the use of the product if any 
of the following tests are met: 
o An unreasonable temporal relationship between administration of the product 
and the onset on the AE (e.g., the event occurred either before, or too long after 
administration of the product for it to be considered product-related); 
o A causal relationship between the product and the AE is biologically implausible 
(e.g., death as a passenger in an automobile 
accident); 
o A clearly more likely alternative explanation for the AE is present (e.g., typical 
adverse reaction 
to a concomitant 
drug and/or typical disease-related 
event). 
 
Consider 
the 
following 
when assessing 
causality: 
• Temporal associations 
between 
the agent 
and 
the event 
• Cessation or 
rechallenge 
• Compatibility with known class effect 
• Known effects of concomitant medications 
• Pre-existing 
risk 
factors 
• A plausible mechanism 
• Concurrent illnesses 
 
8.2.3 Expectedness 
Sponsor will be responsible for determining whether an AE is expected or unexpected. An 
AE will be considered unexpected if the nature, severity, or frequency of the event is not 
consistent with 
the risk information previously 
described for 
the study agent. 
 
8.3 Time Period and Frequency for Event Assessment and Follow-up 
The occurrence of an AE or SAE may come to the attention of study personnel during study 
visits and interviews of a study participant presenting for medical care, or upon review by a 
study monitor. All AEs including local and systemic reactions not meeting the criteria for 
SAEs will be captured on the appropriate eCRF. Information to be collected includes event 
description, dates and times of onset and resolution, clinician’s assessment of severity, 
assessment of relatedness to study drug (assessed only by those with the training and 
authority to make  a diagnosis), and action taken. All AEs occurring while on study must be 
documented appropriately regardless of relationship. All AEs will be followed to adequate 
resolution. 
 
Any medical condition that is present at the time that the participant is screened will be 
considered as baseline and not reported as an AE. However,  if the study participant’s 
condition deteriorates at any time during the study, it will be recorded as an AE. UPs will be 
recorded in the data collection system throughout the study. 


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Changes in the severity of an AE will be documented to allow an assessment of the duration 
of the event at each level of severity to be performed. AEs characterized as intermittent 
require documentation of onset and duration of each episode. 
 
The Investigator will record all reportable events with start dates occurring any time after 
informed consent is obtained until the AE has resolved, stabilized, or a new chronic baseline 
has been established. At each study visit, the Investigator will inquire about the occurrence 
of AE/SAEs since the last visit. Events will be followed for outcome information until 
resolution or stabilization. 
 
8.4 Reporting Procedures 
8.5 Adverse Event Reporting 
All AEs including those of Special Interest, regardless of relatedness to the study drug, must 
be fully and completely documented on the AE eCRF and in the subject’s medical notes. The 
following attributes must be assigned: event description, dates and times of onset and 
resolution, clinician’s assessment of severity, assessment of relatedness to study drug (either 
related or not related), and action taken. The Investigator may be asked to provide 
additional 
follow-up information. 
 
In the event that  a subject is withdrawn from the study because of an AE, it must be 
recorded on the eCRF. The subject must be followed and treated by the Investigator until the 
AE has resolved, stabilized, or a new chronic baseline has been established. 
 
The Investigator must report all observed AEs and all reported AEs. At each visit the 
Investigator will ask the subject  a nonspecific question (e.g., “Have you noticed anything 
different since your last visit?”) to assess whether any AEs have been experienced since the 
last report or visit. AEs will be identified and documented on the AE page of the eCRF in 
appropriate medical terminology. The severity and the relationship to the study drug will be 
determined 
and reported on the 
eCRF (see Sections 8.1.1 
and 8.2.2). 
 
Note that any intermittent or as-needed (“PRN”) use of medication (and specifically any 
newly prescribed medication) during the course of  a study may indicate the occurrence of 
an AE that may need to be recorded on both the AE page of the eCRF and the Concomitant 
Medication 
page. 
 
8.5.1 Serious Adverse Event Reporting 
The reporting of SAEs by Sponsor to the Regulatory Authorities is a regulatory requirement. 
Each Regulatory Authority has established  a timetable for reporting SAEs based upon 
established criteria. It is the responsibility of the principal Investigator to report SAEs to the 
Sponsor within 24 hours. 


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All SAEs must be reported immediately (within 24 hours of discovery) to the   Medical 
Monitor or designee. Do not delay in the reporting of  a suspected SAE in order to obtain 
additional information. Any additional information,  if collected,  can be  reported to the 
Sponsor as  a follow-up to the initial report. SAEs will be reported using the SAE forms 
provided. Please remember to give details of the patient identification number or other 
appropriate terminology and ensure the narrative is comprehensive and includes  a 
chronology and 
assessment of 
the event. 
 
At  a minimum, events identified by Bonti to require expedited reporting as serious, 
unexpected, and possibly related to study drug must be brought to the attention of the 
responsible IRB/IEC. For EU member States, Bonti or designee will provide reports of 
suspected unexpected serious adverse reactions (SUSARs) directly to the IECs, as required by 
local legislation. In all other countries, it is the Investigator’s responsibility to provide these 
expedited reports to the responsible IRB/IEC. It is also the Investigator’s responsibility to 
notify the responsible IRB/IEC regarding any 
new 
and significant safety information. 
 
The process for reporting an SAE or study drug overdose is as follows: 
 
• Complete an AE eCRF page. 
• Complete an SAE form—this must include the patient identification number. 
• Complete the narrative, which should be comprehensive and include a chronological 
description and assessment of 
the event. 
• Complete 
the 
cover sheet. 
• Call the Medical Monitor or designee for life-threatening or fatal events (see details 
that follow). 
• Include results of any related laboratory tests or investigations, histopathologic 
examinations, or consultations with other healthcare professionals that serve to 
clarify the nature 
of the 
event, 
the cause of the event, or both. 
• Email the cover sheet and the SAE form (within 24 hours of discovery) to the Medical 
Monitor or 
designee (see details 
that follow). 
 
Follow-up information on  a previously reported SAE should be processed using  a new SAE 
form. Follow-up information includes additions,  deletions, and corrections to the  initial 
report. Previously signed, dated, and emailed forms should not be altered to provide 
follow-up SAE information of any type. The following must be done when providing follow- 
up information: 
 
• Mark the box 
that indicates follow-up information is being provided. 
• Fill out the dates 
on each page of the form that indicates this is a 
follow-up report. 
• Restate the event as it appears on the initial report. If the event has changed, 
indicate, with parentheses, what 
the event was previously per the 
example below: 
 
SERIOUS 
ADVERSE 
EVENT 
Myocardial 
Infarction 
Diagnosis 
or Sign/Symptom 
(previously chest pain) 


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All SAEs must be reported immediately (within 24 hours of discovery) by email to the 
Medical Monitor or designee. Calls related to SAEs should first be directed to the Medical 
Monitor or 
designee. 
Bonti or designee will provide the Investigator with alternative contact information if the 
Medical Monitor will not be available. 
 
These events will be reported within 24 hours of discovery, particularly for life-threatening 
or fatal events, and the Investigator should continue to provide reports to the IRB/IEC, as 
required. In the event of any SAE (other than death), the patient will be instructed to contact 
the Investigator (or Medical Monitor or designee) using the telephone number provided in 
the I
CF. All subjects experiencing an SAE will be seen by the Investigator or designee as soon 
as is feasible following the report of the SAE. 
 
All SAEs will continue to be followed until the end of the Study or until such events have 
resolved or the Investigator, in conjunction with the Sponsor, deems them to be chronic or 
stable. 
 
SAEs occurring up to 30 days after the study follow up period should be reported if in the 
judgement of the Investigator there is “a reasonable possibility” that the event may have 
been caused by the product. 
 
8.5.2 Reporting of Pregnancy 
Females that may be able to get pregnant will be required to take pregnancy test before 
study agent administration. The results of the pregnancy testing must be negative in order 
to be in the study. 
 
All female subjects who may be able to get pregnant must agree to use either  a highly 
effective method of contraception with failures rates less than 1% per year or dual methods 
of contraception with overall failures rates less than 1% per year from the day of dosing until 
3 months afterwards. Female subjects who underwent sterilization must have initiated the 
procedure at least  3 months prior to the day of dosing. Female subjects using oral 
contraception must have initiated treatment at least 2 months prior 
to the day of dosing. 
 
In the event that a female subject does become pregnant at any time during the study, the 
Investigator must notify the Medical Monitor or designee within 48 hours of learning about 
the 
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The Investigator will be required to complete the Pregnancy Report/Outcome Form and any 
additional documents provided by the Sponsor, follow the subject through the pregnancy 
term, and report to the Medical Monitor or designee the course of the pregnancy, including 
perinatal or neonatal outcome. 
 
Information on the status of the mother and the child will be forwarded to the Medical 
Monitor or designee using the Pregnancy Report/Outcome Form. Any premature 
termination of the pregnancy will also be reported on this 
form. 
 
Although pregnancy occurring in  a clinical study is not considered to be an SAE, any 
pregnancy complication or elective termination of  a pregnancy for medical reasons will be 
recorded as an AE and will be followed as such. A spontaneous abortion is considered to be 
an SAE. 
 
8.6 Study Halting Rules 
See Section 
4.1.1. 
 
8.7 Safety Oversight 
The study SRC including the Investigators, Medical Monitor, Study Director as well as other 
ad hoc representatives as appropriate will regularly monitor all aspects of patient safety 
throughout this  study. The SRC will review all available data in  a blinded manner (may 
include: vital signs, ECGs clinical laboratory tests, incidence of SAE and TEAE) to assess the 
safety of each dose level 
of EB-001 prior to escalating 
to the next dose level. 
 
8.8 Risk Management of 
Prolonged Respiratory Compromise 
Subjects may develop adverse effects indicative of spread of toxin, including  a potentially 
prolonged course of respiratory compromise. If there were to be  a significant respiratory 
event, the study site is located inside an acute care hospital. All subjects have access 24/7 to 
a fully-functional code blue team (including personnel expert in managing airways and 
respiratory emergencies). In addition, the study site is located 100 yards from the hospital 
emergency room so subjects can be quickly and easily transferred after stabilization by the 
code team. 
 
If there is any significant respiratory event in the study i.e., profound hypoxia, respiratory 
depression, sedation etc., the study site and staff will follow usual standard of care which 
may include verbal and physical stimulation, high flow oxygen via face mask or big-mask, 
airway management, and calling for the hospital code team for immediate transfer to the 
emergency room once stabilized, if required. Subjects who do not respond to these 
measures may require endotracheal intubation and mechanical ventilation. Opiate reversal 
agents may 
be 
used in 
subjects who received opioid rescue medications. 
 
In addition, systemic toxicity of EB-001 may be treated with a multi-valent 
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9 CLINICAL MONITORING AND COMPLIANCE 
The Sponsor representatives and regulatory authority inspectors are responsible for 
contacting and visiting the Investigator for the purpose of inspecting the facilities and, upon 
request, inspecting the various records of the study (e.g., eCRFs and other pertinent data), 
provided that subject confidentiality is 
respected. 
 
The study monitor is responsible for inspecting the eCRFs at regular intervals throughout the 
study to verify the following: adherence to the protocol; completeness, accuracy, and 
consistency of the data; and adherence to local regulations on the conduct of clinical 
research. The  monitor should have access to subject medical records and other  study- 
related records needed to verify the entries on the eCRFs. The Investigator must agree to 
cooperate with the monitor to ensure that any problems detected in the course of these 
monitoring visits are resolved. 
 
In accordance with ICH Good Clinical Practice (GCP) and the Sponsor audit plans, this study 
may be selected for an audit. Inspection of site facilities (e.g., pharmacy, drug storage areas, 
laboratories, etc.) and review of study-related records may occur in order to evaluate the 
trial conduct and compliance with the protocol, ICH  GC
P, and applicable regulatory 
requirements. 
 
A separate clinical monitoring plan (CMP) will describe in detail who  will conduct the 
monitoring, at what frequency monitoring will be done, at what level of detail monitoring 
will be performed, and the distribution of monitoring reports. A CMP ordinarily should focus 
on preventing or mitigating important and likely risks, identified by  a risk assessment, to 
critical data and processes. The types (e.g., on-site, centralized), frequency (e.g., early, for 
initial assessment and training versus throughout the study), and extent (e.g., 
comprehensive (100% data verification) versus targeted or random review of certain data 
(less than 100% data verification)) of monitoring activities will depend on a range of factors, 
considered during the risk assessment, including the complexity of the study design, types 
of study endpoints, clinical complexity of the study population, geography, relative 
experience of the PI and of the Sponsor with the PI, electronic data capture, relative safety 
of the study agent, 
stage of the study, and quantity of data. 
 
10 STATISTICAL CONSIDERATIONS 
10.1 Statistical and Analytical Plans 
A formal statistical and analytical plan (SAP) will be completed prior to database lock and 
unblinding of the study data. 
 
10.2 Statistical Hypotheses 
The primary efficacy objective is to estimate the reduction of pain with EB-001, assessed as 
the 
difference in AUC 
for 
the NPRS pain scores over the 12-96 hours postsurgical period. 


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The null hypothesis is that the AUC for the EB-001 arm is greater than or equal to that of the 
placebo arm. The alternative hypothesis is that the AUC for EB-001 is smaller (indicating less 
pain) than that for placebo. 
 
H0: AUCEB-001 ≥ AUCPlacebo 
HA: AUCEB-001 < AUCPlacebo 
While not  a formally powered study,  a one sided hypothesis that the AUC for NPRS and 
NPRS-A will be 
used to inform 
the primary clinical 
hypothesis and support this objective. 
 
10.3 Analysis Populations 
The modified Intent to Treat (mITT) population will include all randomized patients who 
receive study drug. All efficacy analyses will be performed using this population. Analyses 
will be performed on subjects using their 
randomized treatment group. 
 
The Per Protocol (PP) population will include all subjects in the mITT population with no 
major protocol violations. The primary efficacy variable will also be analyzed using this 
population. 
 
The Safety population will include all subjects exposed to any amount of study drug. All 
safety analyses will be performed using 
the safety population. 
 
Analyses of using the PP and Safety populations will analyze subjects according to the 
treatment received. In the event that the subject receives the wrong treatment, they will be 
excluded from 
the per protocol population. 
 
10.4 Description of Statistical Methods 
10.4.1 General Approach 
Data will be summarized by dose of EB-001, across all subjects who received EB-001, and 
across all subjects who received placebo. 
 
All continuous variables including oxygen saturation level documented every 2 hours will be 
summarized using descriptive statistics of mean, median, standard deviation, minimum, and 
maximum. Categorical variables will be summarized using descriptive statistics of number 
and percentage of patients in each category. The 95% confidence intervals may be shown as 
appropriate. 
 
Statistical hypothesis 
testing will 
be 
performed, 
and 
one-sided p-values will be 
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10.4.2 Analysis of the Primary Efficacy Endpoint(s) 
The primary endpoint is the area under the curve (AUC) of subject’s assessment of pain at 
rest using the Numeric Pain  Rating Scale (NPRS) between 12 and 96-hour post-surgery 
(AUC
12-96). 
 
The primary endpoint will be analyzed using Analysis of variance (ANOVA) techniques with 
Treatment as the independent variable. Comparisons of the treatment arms to placebo will 
be performed using Dunnet’s test. Additional covariates may be included in the model as 
exploratory analyses. Specifics of the analysis methodology and exploratory analyses will be 
defined in the SAP
. 
 
10.4.3 Analysis of the Secondary Endpoint(s) 
Continuous secondary endpoints will be analyzed using similar methods as specified for the 
primary endpoint. Categorical endpoints (such as PGA) will be summarized and treatments 
compared using Fishers Exact, Chi-Square, or Cochran-Mantel- Haenszel techniques as 
appropriate. All secondary analyses will be specified in the detailed Statistical Analysis Plan 
(SAP). 
 


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10.5 Sample Size 
Subjects will be allocated to receive either EB-001 or placebo in a 1:1 ratio in Cohorts 1-3, a 
4:1 ratio in Cohort 4,  a 2:1 ratio in Cohort 5,  a 3:1 Ratio in Cohort 6, and  a 5:1 ratio in 
Optional Cohort 7 in Stage 1 stratified by ethnicity (Hispanic and non-Hispanic) starting from 
Cohort 2. The planned total sample size in Stage 1 will be up to 40-58 subjects (up to 24-39 
for EB-001 and up to 16-19 for placebo)  (Figure  1). Optional Cohort  7 will be considered 
after dosing of subjects in Cohorts 1-6. 
 
Subjects in each arm of Stage  2 will be randomly allocated to receive either EB-001 or 
placebo. The planned total sample size will be 66 subjects (44 for EB-001 and 22 for placebo) 
in Stage 2 stratified by ethnicity (Hispanic and non-Hispanic) (Figure 1). 
 
Sample size of this study is not based on formal computations. However, 22 for active and 22 
for placebo provide ~67% power. This power is based on one-sided alpha of 0.05,  a mean 
baseline maximum pain score of 7.5, AUC12-96 ~440 with no drug effect, the delta AUC of 
110 (drug and placebo 
difference), and SD of 170 
AUC12-96. 
 
10.6 Measures to Minimize Bias 
10.6.1  Enrollment/ Randomization/ Blinding Procedures 
Subjects who meet the enrollment criteria will be enrolled into sequential cohorts in Stage 1 
or various arms in Stage 2. Subjects are considered to be randomly assigned to the study 
when they are assigned to receive either EB-001 or placebo. Subjects will be randomly 
allocated to receive either EB-001 or placebo stratified by ethnicity (Hispanic and non- 
Hispanic) starting from Cohort 2. In Stage 1, subjects in cohorts 1, 2, and 3 will receive active 
or placebo drug in a 1:1 ratio, in which subjects in the sentinel groups of these cohorts will 
receive active or placebo drug in  a 1:2 ratio. Subjects in cohort  4 will receive active or 
placebo drug in a 4:1 ratio. Subjects in cohort 5 will receive active or placebo drug in a 2:1 
ratio. Subjects in cohort 6 will receive active or placebo drug in a 3:1 ratio, in which subjects 
in the sentinel group will receive active or placebo drug in a 1:1 ratio. In the optional Cohort 
7 of Stage 1, subjects will receive active or placebo drug in a 5:1 ratio. 
 
In Stage 2, there will be 2 doses of EB-001 (to be determined by the SRC after last dosing of 
last subject of Stage 1) 
and placebo in a 1:1:1 ratio for a 
total of 66 subjects. 
 
Each cohort will have a fixed dose of EB-001. The study in both stages will be conducted in a 
blinded manner (single-blind in Stage 1, double-blind in Stage 2). Study drugs between EB- 


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001 and the placebo vials will be identical in appearance. Study site personnel who prepare 
the 
study drug will not be involved in safety and efficacy assessment. 
 
There will be an unblinded independent dispenser who will prepare and dispense EB-001 or 
placebo for administration in  a blinded manner to subjects. The Investigator and site 
personnel, study subjects, and Sponsor personnel, unless otherwise specified, will be 
unaware of whether subjects are receiving EB-001 or placebo until the study is formally 
unblinded. 
 
10.6.1.1  Subject Numbering 
Patients who have signed the ICF to begin screening procedures will be entered into the 
electronic data capture (EDC) system. The site will assign  a  3-digit site-specific sequential 
screening number at that time. The unique patient identification number will consist of  a 
3-digit original site number followed by  a  3-digit screening number. The patient will keep 
the same number throughout the study. Upon randomization,  a unique  4-digit study- 
specific randomization 
number will be assigned. 
 
In the circumstance, where a patient is randomly assigned to treatment but does not receive 
the study drug, the study coordinator/research nurse must immediately inform the 
unblinded CRA that the study 
drug was not administered. 
 
10.6.2 Evaluation of Success of Blinding 
10.6.2.1 Blinding at the Study Site 
Study treatment group information (active  drug vs placebo) will  remain blinded to  the 
subject and also to all blinded members of the study team at the study site. There will be an 
unblinded independent dispenser who will prepare and dispense EB-001 or placebo for 
administration in a blinded manner to subjects. Study site personnel who prepare the study 
drug will 
not be involved in safety and efficacy assessment. 
 
Investigators, coordinators, and nurses who are responsible for reviewing potentially 
unblinded medical data or who may have access to it (including all routine laboratory tests, 
imaging, and AEs)  must not discuss  any unblinded information or results with the site 
personnel responsible for blinded study assessments. 
 
10.6.2.2 Blinding/Unblinding of Sponsor Personnel 
During this  study, staff of Bonti and designee will be unblinded to treatment allocation in 
Stage 1, and blinded to treatment allocation in Stage 2, except as described in this section 
and in the Site Blinding Plan. The periodic SRC reviews will be performed in  a blinded 
manner unless the data warrant unblinding due to safety concerns. It is assumed that the 
need to unblind a study subject’s treatment assignment will occur in the setting of an SAE, 
and therefore, all procedures for the reporting of a SAE must be followed (see Section 8.5.1). 


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Procedures for emergency unblinding are described in Section 10.6.3. These procedures 
ensure that neither study blinded monitoring staff nor the Investigator and other site staff 
who are blinded have premature access to the study subjects’ treatment assignments. Upon 
notification of an unblinding event, the Sponsor will assess the need for potentially 
removing 
the unblinded 
personnel 
from 
the trial. 
 
10.6.3 Breaking the Study Blind/Participant Code 
An Investigator at  a site may break the blind in the event of an immediate medical 
emergency, where knowledge of the study subject’s treatment assignment (EB-001 or 
placebo) must be known in order to facilitate appropriate emergency medical treatment. In 
these situations, the Investigator must first attempt to contact the Medical Monitor or 
designee before unblinding  a subject’s treatment identity in order to obtain concurrence 
that unblinding  a study subject’s treatment assignment is necessary. If circumstances 
preclude contacting the Medical Monitor or designee, each instance of unblinding must be 
reported to Sponsor within 24 hours. The Medical Monitor or designee may break the blind 
internally in the event of SAE(s), which require expedited reporting to regulatory 
authorities. Any other requests to reveal  a subject’s treatment identity must be requested 
of, and approved by the Medical Monitor or designee. If a study subject’s treatment identity 
is unblinded by the study site, the unblinding must be reported to Bonti and documented on 
the eCRF as  a deviation. Upon notification of an unblinding event, the Sponsor will assess 
the need for potentially removing the unblinded personnel from the trial. If  a subject’s 
treatment identity is unblinded, the subject will be withdrawn from the study and will 
complete the Early Termination 
procedures 
describe in Section 
5.4. 
 
In an emergency situation in which the Investigator believes that the identity of  a study 
subject’s treatment assignment is necessary to treat the subject, the study subject’s 
treatment assignment may be obtained from the randomization list. Details of the process 
to be followed are provided in the study manual(s) provided to the site. In the event that 
the treatment assignment is unblinded, Bonti or designee will be notified immediately that 
the blind has been broken, but will not be informed of the actual treatment assignment of 
the subject unless required for SAE reporting or other specific reason. Other study team 
personnel will remain 
blinded unless 
unblinding is necessary for 
the safety of the subject. 
 
The Investigator or designee is responsible for ensuring that the instructions on how to 
perform  a code break are stored safely, that their location is known, and that access is 
readily available to 
the relevant staff in case of an emergency. 
 
11 SOURCE DOCUMENTS AND ACCESS TO SOURCE DATA/DOCUMENTS 
Each participating site will maintain appropriate medical and research records for this trial, 
in compliance with ICH E6 and regulatory and institutional requirements for the protection 
of confidentiality of participants. 


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The clinical site participating in this study are required to submit clinical data for each 
enrolled subject via an EDC system, using an eCRF. Site personnel will be trained on the EDC 
system before receiving access to the system. The Sponsor or designee is responsible for 
maintaining a record of all system users. The participants of the study will not be identified 
by name on any study documents to be collected by the Sponsor (see Section 13.4). 
 
All clinical information requested in this protocol will be recorded on the eCRF provided by 
the CRO (or via other data collection methods, e.g. electronic laboratory data transfer). The 
principal Investigator is responsible for reviewing all eCRFs, verifying them for accuracy, and 
approving them via an electronic signature. Copies of the completed eCRFs, saved to disk in 
.pdf format, will be sent to the Investigator’s site 
at the 
completion of the 
study. 
 
Additional source data may include, but are not limited to, hospital records, clinical and 
office charts, laboratory notes, memoranda, participant’s memory aids or evaluation 
checklists, pharmacy dispensing records, recorded audio tapes of counseling sessions, 
recorded data from automated instruments, copies or transcriptions certified after 
verification as being accurate and complete, photographic negatives, and participant files 
and records kept at the pharmacy, at the laboratories, and medico-technical departments 
involved in the clinical trial. 
 
12 QUALITY ASSURANCE AND QUALITY CONTROL 
See Section 
9. 
 
13 ETHICS/PROTECTION OF HUMAN SUBJECTS 
13.1 Ethical Standard 
The Investigator will ensure that this study is conducted in full conformity with Regulations 
for the Protection of Human Subjects of Research codified in 45 Code of Federal Regulations 
(CFR) Part 46, 21 CFR Part 50, 21 CFR Part 56, 
and/or the ICH E6. 
 
13.2 Institutional Review Board 
The protocol, informed consent form(s), recruitment materials, and all participant materials 
will be submitted to the IRB for review and approval. Written approval of both the protocol 
and the consent form must be obtained before any participant is enrolled. Any amendment 
to the protocol will require review and approval by the IRB before the changes are 
implemented to the  study. All changes to the consent form will be IRB approved;  a 
determination will be made regarding whether previously consented participants need to be 
re-consented. 


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13.3 Informed Consent Process 
The Sponsor must review the draft ICF prepared by the Investigator prior to submission to 
the IRB for 
approval. An IRB-approved copy of the ICF will be forwarded 
to 
the Sponsor. 
 
The ICF documents the study-specific information the Investigator provides to the subject 
and the subject’s agreement to participate. Among other things, the Investigator will fully 
explain in layman’s terms the nature of the study, along with the aims, methods, potential 
risks, and any discomfort participation may entail. The subject must sign and date the ICF 
before any study-related procedures are performed. The original and any amended signed 
and dated ICF(s) must be retained in the subject’s file at the study site and a copy must be 
given to the subject. 
 
13.4 Participant and Data Confidentiality 
The Investigator must ensure that each subject’s anonymity is maintained as described 
below. On the eCRFs or other documents  submitted to the Sponsor, subjects must be 
identified by no more than their initials, date of birth, and a Subject Identification Number
. 
Documents that are not for submission to the Sponsor (e.g., signed ICFs) should be kept in 
strict confidence by the Investigator in compliance with applicable regulations and ICH GCP 
E6 Guidelines  (FDA 2015). Participant confidentiality is strictly held in trust by the 
participating Investigators, their  staff,
 and the Sponsor(s) and their agents. This 
confidentiality is extended to cover testing of biological samples and genetic tests in 
addition to the clinical information relating to participants. Therefore, the study protocol, 
documentation, data, and all other information generated will be held in strict confidence. 
No information concerning the study or the data will be released to any unauthorized third 
party without prior written approval of 
the Sponsor. 
 
The Investigator and institution must permit authorized representatives of the Sponsor, of 
regulatory agencies, and the IRB direct access to review the subject’s original  medical 
records for verification of study-related procedures and data. Direct access includes 
examining, analyzing, verifying, and reproducing any records and reports that are needed for 
the evaluation of the study. The Investigator is obligated to inform the subject in the ICF that 
the above 
named representatives may 
review 
study-related records 
from 
subjects. 
 
13.4.1  Research Use of Stored Human Samples or Data 
Samples and data collected under this protocol may be used to study the safety and efficacy 
of EB-001. All data and materials created from the samples will be the property of the 
Sponsor. Samples collected will be stored in either the laboratory of the Sponsor or the 
laboratory of a company contracted to work with the Sponsor with a proper tracking system. 
Access to study samples will be limited to laboratory personnel working for the Sponsor or 
contracted to the Sponsor, who are authorized 
to 
perform analyses. 


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Samples collected may be stored for up to 10 years after the end of the study (the end of the 
study occurs when a final study report is written). 
 
13.5 Future Use of Stored Specimens 
Additional tests may be conducted on subject blood samples to better understand or 
develop treatments for pectoral muscle pain, and/or for safety issues that may arise in the 
future. 
 
During the conduct of the study, an individual participant can choose to withdraw consent 
to have biological specimens stored for future research. However, withdrawal of consent 
with regard to biosample storage will not 
be possible after the study is completed. 
 
13.6 Protocol Amendments and Study Termination 
Protocol amendments must be made only with the prior approval of the Sponsor. 
Agreement from the Investigator must be obtained for all protocol amendments and 
amendments to the ICF. The IRB must be informed of all amendments and give approval 
for any amendments before the changes are implemented to the study. The Investigator 
must send a copy of the 
approval letter from 
the 
IRB to the Sponsor. 
 
Both the Sponsor and the Investigator reserve the right to terminate the study, according to 
the study contract. The Investigator should notify the IRB in writing of the trial’s completion 
or early termination and send a copy of the notification to the Sponsor. 
 
14 DATA HANDLING AND RECORD KEEPING 
14.1 Data Collection and Management Responsibilities 
Data collection is the responsibility of the clinical trial staff at the site under the 
supervision of the site Investigator. The Investigator is responsible for ensuring the 
accuracy, completeness, 
legibility, 
and timeliness 
of 
the 
data reported. 
 
All source documents should be completed in  a neat, legible manner to ensure accurate 
interpretation of data. Black or blue ink is required to ensure clarity of reproduced copies. 
When making changes or corrections, cross out the original entry with  a single line, and 
initial and date the change. DO NOT ERASE, OVERWRITE, OR USE CORRECTION FLUID OR 
TAPE ON THE ORIGINAL. 
 
Data reported in the eCRF derived from source documents should be consistent with the 
source documents or the discrepancies should be explained and maintained in the 
participant’s official study record. 
 
Clinical data (including AEs, concomitant medications, and expected adverse reactions data) 
and clinical laboratory data will be entered into Axiom Fusion,  a 21 CFR Part 11-compliant 
data capture system provided by the Axiom Real-time Metrics. The data system includes 


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password protection and internal quality checks, such as automatic range checks, to identify 
data that appear inconsistent, incomplete, or inaccurate. Clinical data will be entered 
directly from 
the source 
documents. 
 
14.2 Study Records Retention and Availability 
The Investigator must make study data accessible to the study  monitor, other authorized 
representatives of the Sponsor, and Regulatory Agency inspectors upon request.  A file for 
each subject must be maintained that includes the signed ICF and the Investigator’s copies 
of all source documentation related to that subject. The Investigator must ensure the 
reliability and availability of source documents from which the information on the eCRF was 
derived. 
 
Investigators are required to maintain all study documentation, including copies of eCRFs, 
ICFs, and adequate records for the receipt and disposition of all study medications, for  a 
period of  2 years following the FDA or other regulatory approval date of the drug, or until 
2 years after the drug investigational program is discontinued, unless  a longer period is 
required by applicable law or regulation. The Investigator must not discard any records 
unless given authorization by the Sponsor. 
 
Subject identity information will be maintained for 15 years unless applicable law or 
regulation requires a longer period. 
 
14.3 Protocol Deviations 
A protocol deviation is any noncompliance with the clinical trial protocol or GCP 
requirements. The non-compliance may be either on the part of the participant, the 
Investigator, or the study site  staff. As  a result of deviations, corrective actions may be 
developed 
by 
the site and implemented promptly. 
 
These practices 
are consistent with ICH E6: 
 
• 4.5 Compliance with Protocol, sections 4.5.1, 4.5.2, and 4.5.3 
• 5.1 Quality Assurance and Quality Control, 
section 5.1.1 
• 5.20 
Noncompliance, sections 5.20.1, 
and 5.20.2. 
 
All deviations must be addressed in study source documents and transcribed into the eCRF 
(as applicable). Protocol deviations must be sent to the local IRB per their guidelines. The 
site Investigator  and study staff are  responsible  for knowing and adhering to  their  IRB 
requirements. 
 
14.4 Publication and Data Sharing Policy 
All publication and authorship rights are delineated in 
the Clinical Study Agreement. 


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SAP_001.pdf: 
NCT03429556 
 
Study ID: EB001-ABD201 
 
Title: A Phase 2 Study to Evaluate Safety and Efficacy of EB-001 Intramuscular (IM) Injections 
in Reducing Musculoskeletal Pain in Subjects Undergoing Elective Abdominoplasty Surgery 
 
Statistical Analysis Plan Version 4.0: 09 May 2018 
 


Sponsor: Bonti, Inc. 
 
Statistical Analysis Plan Version 1.0 
Protocol Number: EB001-ABD201 
 
Effective Date: 07NOV2018 
CONFIDENTIAL 
 
 
 
STATISTICAL ANALYSIS PLAN 
 
 
 A Phase 2 Study to Evaluate Safety and Efficacy of EB-001 Intramuscular (IM) Injections in 
Reducing Musculoskeletal Pain in Subjects Undergoing Elective Abdominoplasty Surgery 
 
Protocol Number: EB001 ABD201 
Protocol Version 4.0 (09MAY2018) 
 
SPONSORED BY 
Bonti, Inc. 
This document is confidential and proprietary to Bonti, Inc.  Acceptance of this document constitutes agreement by the 
recipient that no unpublished 
information contained herein will be reproduced, published, or otherwise disclosed without the 
prior written approval of Bonti, Inc., except that this document may be disclosed to appropriate Institutional Review Boards 
under the condition that they keep the information confidential. 
 
DocuSign Envelope ID: 1F17F32E-45D7-4787-B080-B75077612E44
 


Sponsor: Bonti, Inc. 
 
Statistical Analysis Plan Version 1.0 
Protocol Number: EB001-ABD201 
 
Effective Date: 07NOV2018 
CONFIDENTIAL                                              Page 2 of 30 
 
DOCUMENT VERSION CONTROL 
Version Number 
Date 
Comments/Changes 
V1.0 
07NOV2018 
Final SAP 
 
 
 
 
 
 
 
 
 
 
 
 
DocuSign Envelope ID: 1F17F32E-45D7-4787-B080-B75077612E44
 


Sponsor: Bonti, Inc. 
 
Statistical Analysis Plan Version 1.0 
Protocol Number: EB001-ABD201 
 
Effective Date: 07NOV2018 
CONFIDENTIAL                                              Page 3 of 30 
 
DocuSign Envelope ID: 1F17F32E-45D7-4787-B080-B75077612E44
 


Sponsor: Bonti, Inc. 
 
Statistical Analysis Plan Version 1.0 
Protocol Number: EB001-ABD201 
 
Effective Date: 07NOV2018 
CONFIDENTIAL                                              Page 4 of 30 
 
TABLE OF CONTENTS 
 
Contents 
LIST OF IN-TEXT TABLES AND FIGURES 
............................................................ 6 
LIST OF ABBREVIATIONS (COMMONLY USED) 
.................................................. 7 
1. PURPOSE OF THE ANALYSES 
...................................................................... 9 
2. PROTOCOL SUMMARY 
.................................................................................. 9 
2.1 
Study Objectives 
................................................................................................................................ 
9 
 
 
2.1.2 Efficacy ........................................................................................................................................ 
9 
2.2 
Overall Study Design and Plan 
........................................................................................................... 
9 
2.3 
Study Population 
.............................................................................................................................. 
10 
2.4 
Treatment Regimens 
........................................................................................................................ 
11 
 
 
2.4.2 Comparator Group ..................................................................................................................... 
11 
2.4.3 Planned Dose Cohorts ............................................................................................................... 
11 
3. GENERAL ANALYSIS AND REPORTING CONVENTIONS .......................... 11 
4. ANALYSIS POPULATIONS ........................................................................... 13 
4.1 
Efficacy Population 
........................................................................................................................... 
13 
 
 
4.3 
Disposition of Subjects 
..................................................................................................................... 
13 
4.4 
Major Protocol Deviations ................................................................................................................ 
13 
 
 
 
 
 
 
 
 
 
 
6. MEASUREMENTS OF TREATMENT COMPLIANCE 
.................................... 14 
7. EFFICACY EVALUATION 
.............................................................................. 15 
7.1 
Overview of Efficacy Analysis Issues ............................................................................................... 
15 
7.1.1 Handling of Dropouts or Missing Data 
........................................................................................ 
15 
7.1.2 Assessment Time Windows........................................................................................................ 
15 
7.2 
Efficacy Outcomes 
........................................................................................................................... 
15
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Sponsor: Bonti, Inc. 
 
Statistical Analysis Plan Version 1.0 
Protocol Number: EB001-ABD201 
 
Effective Date: 07NOV2018 
CONFIDENTIAL                                              Page 5 of 30 
7.2.1 Primary Efficacy Endpoint .......................................................................................................... 
16 
7.2.2 Secondary Efficacy Endpoints 
.................................................................................................... 
16 
7.3 
Analysis Methods 
............................................................................................................................. 
16 
7.3.1 AUC Outcomes .......................................................................................................................... 
16 
7.3.2 NPRS and NPRS-A Outcomes 
................................................................................................... 
17 
7.3.3 Patient Global Assessment (PGA) of Pain Control ..................................................................... 
17 
7.3.4 Rescue Medication 
..................................................................................................................... 
17 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
11. INTERIM ANALYSES AND DATA MONITORING 
.......................................... 24 
12. CHANGES TO THE ANALYSES PLANNED IN THE PROTOCOL 
................. 24 
 
 
 
 
 
 
 
 
 
 
 
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Sponsor: Bonti, Inc. 
 
Statistical Analysis Plan Version 1.0 
Protocol Number: EB001-ABD201 
 
Effective Date: 07NOV2018 
CONFIDENTIAL                                              Page 6 of 30 
 
LIST OF IN-TEXT TABLES AND FIGURES 
Table 7-1 
Table of Morphine Milligram Equivalents 
....................................... 
18 
 
 
 
 
 
 
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Sponsor: Bonti, Inc. 
 
Statistical Analysis Plan Version 1.0 
Protocol Number: EB001-ABD201 
 
Effective Date: 07NOV2018 
CONFIDENTIAL                                              Page 7 of 30 
 
 
LIST OF ABBREVIATIONS (COMMONLY USED) 
ADaM 
Analysis Data Model 
ADL 
Activities of Daily Living 
AE 
Adverse Event 
ANOVA 
Analysis of variance 
ATC 
Anatomical Therapeutic Chemical 
AUC 
Area Under the Curve 
BMI 
Body Mass Index 
BP 
Blood Pressure 
CRF 
Case Report Form 
CSR 
Clinical Study Report 
CSU 
Clinical Study Unit 
EB-001 
Botulinum Neurotoxin Serotype E Drug Product 
ECG 
Electrocardiogram 
EOS 
End of Study 
ET 
Early Termination 
FEV1 
Forced Expiry Volume 1 
FVC 
Forced Vital Capacity 
GCP  
Good Clinical Practice 
HIV 
Human Immunodeficiency Virus 
HR 
Heart Rate 
HSA 
Human Serum Albumin 
ICF  
Informed Consent Form 
ICH 
 
International Conference on Harmonization  
IM  
Intramuscular 
MedDRA 
Medical Dictionary for Regulatory Activities 
mITT 
Modified Intent to Treat 
NPRS 
Numerical Pain Rating Scale  
NPRS-A 
Numerical Pain Rating Scale Administered After an Activity  
MEQ 
morphine milligram equivalents
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Sponsor: Bonti, Inc. 
 
Statistical Analysis Plan Version 1.0 
Protocol Number: EB001-ABD201 
 
Effective Date: 07NOV2018 
CONFIDENTIAL                                              Page 8 of 30 
PACU 
Post-Anesthesia Care Unit 
PFT 
Pulmonary Function Test 
PGA 
Patient Global Assessment 
PP 
Per Protocol 
PR Interval 
Time between the onset of atrial depolarization and the onset 
of ventricular depolarization  
PT 
Preferred Term 
QRS duration 
The interval from the beginning of the Q wave to the 
termination of the S wave, representing the time for 
ventricular depolarization  
QT Interval 
Interval representing the time for both ventricular 
depolarization and repolarization to occur  
QTcB Interval 
QTc interval using Bazett’s correction (msec) = QT/(RR)½, 
where the QT interval is measured in msec and the RR 
interval is measured in seconds  
QTcF Interval 
QTc interval using Fridericia’s correction (msec) = QT/(RR)⅓, 
where the QT interval is measured in msec and the RR 
interval is measured in seconds  
RR Interval 
Time elapsed between two consecutive R-waves. 
SAE 
Serious Adverse Event/Experience 
SAP 
Statistical Analysis Plan 
SD 
Standard Deviation 
SDTM  
Standard Data Table Model 
SOC 
System Organ Class 
SOT 
Spread of Toxin 
SpO2 
Peripheral Capillary Oxygen Saturation 
SRC 
Safety Review Committee 
SVC  
Slow Vital Capacity 
TEAE 
Treatment Emergent Adverse Event 
WHO 
World Health Organization 
 
 
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Sponsor: Bonti, Inc. 
 
Statistical Analysis Plan Version 1.0 
Protocol Number: EB001-ABD201 
 
Effective Date: 07NOV2018 
CONFIDENTIAL                                              Page 9 of 30 
 
1. PURPOSE OF THE ANALYSES 
This statistical analysis plan (SAP) is based on protocol number EB001-ABD201 Amendment 3 
Final Version 4.0 (09May2018) from Bonti. Inc.  The SAP will be signed off before the final 
database lock.  The SAP contains detailed information to aid in the performance of the statistical 
analysis and reporting of the study data for use in the final clinical study report (CSR).  This SAP 
is being written with due consideration of the recommendations outlined in the most recent 
International Conference on Harmonization (ICH) E9 Guideline entitled Guidance for Industry: 
Statistical Principles for Clinical Trials, the most recent ICH E3 Guideline and the Guidance for 
Industry: Structure and Content of Clinical Study and the most recent FDA draft Guidance for 
Industry - Analgesic Indications: Developing Drug and Biological Products, dated February 2014. 
This SAP describes the data sets that will be analyzed and the subject characteristics, safety, and 
efficacy assessments that will be evaluated.  This SAP provides details of the specific statistical 
methods that will be used.  If additional analyses are required to supplement the planned 
analyses described in this SAP, they may be completed and will be identified in the CSR. 
The study was terminated early as per Sponsor’s discretion. The decision was not related to any 
safety findings of the drug. Due to early termination of the study, descriptive summaries will be 
provided but no statistical comparisons will be performed for the data collected prior to the study 
close-out.    
 
2. PROTOCOL SUMMARY 
2.1 Study Objectives 
 
  
 
 
 
   
2.1.2 Efficacy 
To evaluate the efficacy of intraoperative administration of EB-001 IM into the RA muscles in 
reducing the pain and use of rescue pain medications in subjects undergoing elective 
abdominoplasty surgery. Efficacy will be assessed by efficacy endpoints listed in Sections 7.2.1 
and 7.2.2 of the SAP. 
2.2 Overall Study Design and Plan 
This was planned to be a two-stage study but was terminated after 23 subjects were randomized 
in Stage 1.  The following describes the original study design.  The study was intended to be 
conducted at up to two surgical centers that specialize in elective abdominoplasty surgeries and 
to enroll up to 32-74 subjects in Stage 1 and 66 subjects in Stage 2, with up to 56-
DocuSign Envelope ID: 1F17F32E-45D7-4787-B080-B75077612E44
60 subjects 


Sponsor: Bonti, Inc. 
 
Statistical Analysis Plan Version 1.0 
Protocol Number: EB001-ABD201 
 
Effective Date: 07NOV2018 
CONFIDENTIAL                                              Page 10 of 30 
exposed to active drug. The study included a screening visit to determine subject eligibility. On the 
day of surgery, subjects were admitted to an inpatient clinic for 5 days post-operatively (Days 1-
5). Intraoperatively, a single dose of EB-001 IM was given via IM injections into each RA muscles 
per the surgical procedure manual. Follow up visits were planned to be scheduled at days 8, 15, 
and 29. 
The first stage was a placebo-controlled, single-blind (to subject and staff at study site), single 
ascending cohort study stratified by ethnicity (Hispanic and non-Hispanic) starting from Cohort 2. 
Four cohorts (8 subjects per cohort) were planned to be dosed at 4 ascending doses of EB-001. 
An optional Cohort 5 was to be considered. See Section 2.4.3 of the SAP for planned cohort 
details.  
In the event an intolerable dose was identified, a lower (intermediary) dose could have been 
evaluated as proposed by the SRC. This lower dose could have been a repeat of the prior lower 
dose cohort or an intermediary dose between the intolerable dose and prior lower dose cohort.  
In the first stage of the study, if an intolerable dose was identified (see Section 4.1.1 of Protocol), 
a lower dose could be evaluated as proposed by the SRC. This lower dose may be a repeat of the 
prior lower dose cohort or an intermediary dose between the intolerable dose and prior lower dose 
cohort. If the dose was an intermediary dose, a sentinel group consisting of 3 subjects (1 active: 2 
placebo) would be dosed first. The SRC would review all available safety data of the prior sentinel 
group through at least Day 5 post-operatively, and 5 additional subjects (3 active: 2 placebo) 
would be dosed upon approval. 
In addition, if the SRC deemed appropriate, before an intolerable dose was identified, a repeat 
dose, or a dose not exceeding the planned dose of the next cohort could have been evaluated. 
If a repeat or lower dose (i.e., any dose at or lower than prior highest dose evaluated without 
meeting stopping criteria) was to be considered, subjects could be dosed without implementing 
sentinel dosing strategy. 
All dose escalation/adjustments or additional cohorts and corresponding sample size were 
intended to be and were determined by the SRC. 
The second stage was to be a randomized, placebo-controlled, double-blind, parallel 3-arm study. 
In this stage, there would be 2 doses of EB-001 (to be determined by the SRC after last dosing of 
last subject of Stage 1) and placebo in a 1:1:1 ratio for a total of 66 subjects stratified by ethnicity 
(Hispanic and non-Hispanic). The SRC would meet periodically to review safety data. 
 The study was terminated early (after 23 subjects were randomized and dosed) at the discretion 
of the sponsor.  
 
2.3 Study Population 
The study population consists of healthy males or females 23 to 55 years of age, inclusive, 
undergoing elective abdominoplasty surgery (Full length plication from xyphoid to pubis, removal 
of skin/fat flap) under general anesthesia (endotracheal or otherwise) without liposuction.
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Effective Date: 07NOV2018 
CONFIDENTIAL                                              Page 11 of 30 
2.4 Treatment Regimens 
 
 
 
 
 
2.4.2 Comparator Group 
 
2.4.3 Planned Dose Cohorts  
The planned cohorts were as follows: 
Cohort 1 sentinel group (3 subjects; 1 active: 2 placebo) 
 The rest of 
the cohort (5 subjects; 3 active: 2 placebo) will be dosed at the same dose after review of all 
available data by the Safety Review Committee (SRC) is conducted, with safety data through at 
least Day 5 post-operatively. 
Cohort 2 sentinel group (3 subjects; 1 active: 2 placebo) 
 after review of 
all available safety data from the prior cohort through at least Day 5 post-operatively. The rest of 
the cohort (5 subjects; 3 active: 2 placebo) will be dosed after review of all available data by the 
SRC is conducted, with safety data through at least Day 5 post-operatively. 
Cohort 3 sentinel group (3 subjects; 1 active: 2 placebo) 
 after review of 
all available safety data from the prior cohorts through at least Day 5 post-operatively. The rest of 
the cohort (5 subjects; 3 active: 2 placebo) were to be dosed after review of all available data by 
the SRC was conducted, with safety data through at least Day 5 post-operatively. 
Optional Cohort 4 sentinel group (3 subjects; 1 active: 2 placebo) 
 after 
review of all available safety data from the prior cohorts through at least Day 5 post-operatively. 
The rest of the cohort (5 subjects; 3 active: 2 placebo) will be dosed after review of all available 
data by the SRC is conducted, with safety data through at least Day 5 post-operatively. 
Optional Cohort 5 (up to 42 subjects; 2 active: 1 placebo) will be dosed at a dose previously 
assessed after review of all available safety data from the prior cohorts through at least Day 5 
post-operatively. 
In the event an intolerable dose is identified, a lower (intermediary) dose may be evaluated as 
proposed by the SRC. This lower dose may be a repeat of the prior lower dose cohort or an 
intermediary dose between the intolerable dose and prior lower dose cohort.  
After 23 subjects were randomized (enrollment after Cohort 3 was completed), the study 
enrollment was on hold and the study was later terminated at the discretion of the sponsor.    
3. GENERAL ANALYSIS AND REPORTING CONVENTIONS 
This section discusses general policies to be employed in the analysis and reporting of the data 
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sections of this SAP.  When this situation occurs, the rules set forth in the specific section take 
precedence over the general policies. 
All continuous study assessments will be summarized by treatment and time point (as applicable) 
using the descriptive statistics n, mean, SD, median, and range (minimum, and maximum).  All of 
the categorical study assessments will be summarized by treatment and time point (as applicable) 
using frequency counts and rates of occurrence (%).  Changes from baseline for continuous 
outcomes will be presented as their corresponding continuous measures for post-baseline visits.  
All study data will be listed by treatment dose level, subject, and time point (as applicable).  The 
placebo group will consist of the placebo subjects from each of the different cohorts combined. 
For all analyses, the pooled set of placebo subjects from the various cohorts will be considered 
the placebo group. 
No preliminary rounding will be performed; rounding will only occur after the analysis.  To round, 
consider the digit to the right of the last significant digit:  if <5, then round down; if ≥5, then round 
up.  Means and medians will be presented with one more decimal place than the precision of the 
data.  SDs will be presented with two more decimal places than the precision of the data.  
Percentages will be presented with one decimal place.  Minimums and maximums will be 
presented with the same precision as the original data. 
  The domain (Study 
data tabulation Model [SDTM]) and analysis (Analysis Data Model [ADaM]) data sets will be taken 
as input to the  
programs that generate the report-ready tables, figures and listings.  The 
submission ready SDTM and ADaM data sets will be provided to the sponsor along with display 
deliveries. 
For all summaries, the pooled set of placebo subjects from the various cohorts will be considered 
the placebo group. 
No testing will be conducted due to early termination of the study.  
The following conventions will be used throughout the study analysis: 
• Stop Time of dose administration is considered time 0. 
• Assessment visit times are defined by time of treatment administration. 
• Baseline value is defined as the last valid measurement prior to the start treatment 
administration. 
• Change from baseline is defined as post-baseline value minus baseline value. 
• Duration of an AE will be computed in hours in the first 96 hours during confinement and 
thereafter in days as the stop date of the event minus the start date plus 1.  If reported as 
ongoing at the time of database lock, the stop date will be imputed as the date of the last 
visit or the last date of any AE for the subject in the database, whichever is later.  Other 
missing dates will be imputed as described in Table 8-1. 
• The number of days in the study is computed as: [Date of study completion or withdrawal 
minus the date of treatment administration (Day 0)] + 1.   
• If duplicate values are obtained at a given visit (e.g., repeated vital sign measurements), 
the last value will be used unless it is noted that the measurement was in error for that 
value.  
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Values that compromise interpretation will not be used in summaries (e.g., values 


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CONFIDENTIAL                                              Page 13 of 30 
that were obtained post-dose will not be summarized as pre-dose values). 
• If a pre-rescue NPRS is recorded in the same minute as a rescue medication is recorded, 
the NPRS will be assumed to have occurred PRIOR to the administration of rescue.  
o If a subject experiences inadequate analgesic relief and takes non- protocol 
specified rescue medication, they will be treated as ‘discontinued’ from the 
efficacy portion of the study. The date/time of the discontinuation will be 
assumed to be the date/time of the start of non-protocol specified rescue 
captured on protocol deviations eCRF. Early discontinuation from the efficacy 
portion affects the computation of the analgesic endpoints only. 
 
4. ANALYSIS POPULATIONS 
4.1 Efficacy Population 
• The modified Intent to Treat (mITT) population will include all randomized patients who 
receive study drug and have at least one non- missing NPRS assessment within the primary 
endpoint timeline (12-96 hours, inclusive). In addition to the primary analysis of the primary 
endpoint, all efficacy analyses will be performed using this population. Analyses will be 
performed on subjects using their randomized treatment group.  
• All Randomized Subjects:  All participants who are successfully screened and randomized. 
For all efficacy analyses, subjects will be analyzed based on the mITT population.   
4.2 Safety Population 
The Safety population will include all subjects exposed to any amount of study drug. All safety 
analyses will be performed using the safety population and be based upon the actual treatment 
received if different from that randomized. 
4.3 Disposition of Subjects 
All subjects and the populations for which they qualify will be listed.  If a subject is randomized but 
does not complete the surgery or receive study drug, they will not be counted in any analyses.  
Subjects who are screened and who fail screening or withdraw consent prior to randomization or 
are randomized but not treated will be listed and summarized in total and by reason.  Subjects 
who are randomized, subjects who are included in each study population (mITT, and Safety), 
subjects who are treated, subjects who complete follow-up (safety only and safety/efficacy), and 
subjects who withdraw early from the study and the reason for withdrawal will be summarized by 
treatment group and overall in a subject disposition summary table. Subjects who are 
discontinued from the efficacy portion of the study or who discontinue the study but agree to be 
followed for safety will also be presented. 
4.4 Major Protocol Deviations 
A protocol deviation is any noncompliance with the clinical trial protocol or Good Clinical Practice 
(GCP) requirements. All deviations will be addressed in study source documents and transcribed 
into the electronic case report form (eCRF).  All protocol deviations will be designated as major or 
minor prior to database lock by the sponsor’s medical monitor.  
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All protocol deviations will be presented in a by-subject listing. Any site-specific deviations noted 
by the clinical monitors will be documented in the final CSR.  
6. MEASUREMENTS OF TREATMENT COMPLIANCE
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CONFIDENTIAL                                              Page 15 of 30 
Study medication exposure will be provided in a data listing. Because study medication is 
administered at the study center by trained study personnel, compliance with study medication is 
not expected to be an issue and no summary will be provided.  
7. EFFICACY EVALUATION 
7.1 Overview of Efficacy Analysis Issues 
7.1.1 Handling of Dropouts or Missing Data 
If a subject receives protocol specified rescue medication, a windowed LOCF imputation method 
will be used and the pre-rescue pain NPRS/NPRS-A score for each assessment (pain at rest, 
pain after walking) will be carried forward for 4 hours.  Intermittent missing pain scores (due to 
subject sleeping, etc.) will not be imputed, and AUC will be calculated based on non-missing 
values.  
In AUC analyses, no other imputation will be performed for subjects who have missing values due 
to early drop out. In addition, there will be no imputation of missing data for safety or other efficacy 
assessments.   
7.1.2 Assessment Time Windows 
Assessment times will be based on the nominal protocol-specified assessment times.   
7.2 Efficacy Outcomes 
Overall pain assessment at rest using NPRS will be performed every 2 hours ((±15 minutes) post-
dose after the subject is awake and lucid from surgery, until discharge. Assessments will also be 
made after subjects are discharged on Days 6-29 and will be entered into the Pain Assessment 
Diary (see Section 7.1.1.31.1 of the protocol).  
Pain assessment after an activity using NPRS-A will be performed at baseline (prior to surgery), 
every 8 hours (±15 minutes) post-dose on Day 1, and every 6 hours on day 2 and after, after the 
subject is awake and lucid from surgery until discharge. The Investigator will ask subjects to sit up 
in the bed unassisted at an angle of approximately 45 degrees or more, swing legs out, put feet 
down, stand up, and walk approximately 10 feet. Subjects will then be asked to rate their level of 
worst pain when performing the activities using the NPRS-A. NPRS-A will also be assessed at 
each follow-up visit on days 8, 15, and 29 (End of Study (EOS)/ Early Termination (ET)). 
During the in-patient period (up to Day 5), NPRS / NPRS-A assessments scheduled between 
00:00 and 06:00 may be skipped if the subject is sleeping. However, the 12-hour pain assessment 
must be completed even when the assessment falls between 00:00 and 06:00. 
NPRS and NPS-A are ranged based on an 11-point numerical scale, where 0 means no pain and 
10 means the worst pain imaginable. 
In the event rescue medication is used, an assessment of pain using the NPRS prior to 
administering rescue medication will be recorded. If subjects cannot perform NPRS-A prior to 
taking rescue medication due to intolerable pain, this assessment may be omitted.  
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7.2.1 Primary Efficacy Endpoint 
Area under the curve (AUC) of subject’s assessment of pain using NPRS between 12- and 96-
hour post-surgery (AUC12-96).   
7.2.2 Secondary Efficacy Endpoints 
• AUC assessment of overall pain profile using NPRS: 
o Over the first 96 hours post-surgery (AUC0-96)  
o Over the first 72 hours post-surgery (AUC0-72)  
o Over the first 48 hours post-surgery (AUC0-48)  
o Over the first 24 hours post-surgery (AUC0-24)  
o Over the period of 12 to 24 hours post-surgery (AUC12-24)  
o Over the period of time t to 96 hours post-surgery ((AUCt-96), whereas t is any time 
during confinement 
• Pain assessment at rest after discharge using NPRS at Days 6 through 29. 
• Pain assessment after sitting up in the bed unassisted at an angle of approximately 45 
degrees or more, swinging legs out, putting feet down, standing up, and walking 
approximately 10 feet using NPRS-A (NPRS administered after an activity) over the first 
96 hours and at Days 8, 15, 29. 
• Patient global assessment (PGA) of pain control 
• Use of rescue medications over various postsurgical periods 
7.3 Analysis Methods 
7.3.1 AUC Outcomes 
All AUC calculations will be done using the standard trapezoidal rule  
AUC =     ∑
(
�����+�����+1
2
)
�
�=0
∗ (��+1− ��) 
Where:  NPRSi = NPRS at time i, and (Ti+1 – Ti) is the Time difference in hours between time i and 
time i+1. The AUC calculation of NPRS-A will be calculated using the same formula, substituting 
NPRS-Ai in place of NPRS
i. 
In the event that protocol specified rescue medication is used during the time period of AUC 
calculation, for purposes of AUC calculation, the NPRS and/or NPRS-A score taken prior to the 
dispensation of rescue medication will be used as the NPRS and/or NPRS-A score for the 
following 4-hour period and the observed AUC score will be ignored.   
The individual NPRS and NPRS-A scores through Day 5 (prior to discharge) will be presented 
graphically over time by cohort and presented in subject listings.   
The computed AUCs will be listed for the individual subjects along with the respective endpoints 
that they were calculated on. 
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7.3.2 NPRS and NPRS-A Outcomes  
The individual NPRS and NPRS-A outcomes after discharge will be summarized at each time 
point similar to the primary analysis.       
7.3.3 Patient Global Assessment (PGA) of Pain Control 
To assess pain control, each subject will be asked the following question: “Overall, how well your 
pain has been controlled during the last 24 hours?” at 96±2 hours (Days 5), and on Days 8, 15, 
and 29 (EOS/ET), using a 4-point categorical scale (Poor (0), Fair (1), Good (2), Excellent (3)).  
PGA summary tables will include the proportion of subjects with each score, by cohort and time 
point.  PGA scores will be listed. 
7.3.4 Rescue Medication 
Rescue medication when needed is a maximum of 5 doses of 50 μg IV Fentanyl (up to 250 μg 
total) during the first 120 minutes after post-anesthesia care unit (PACU) arrival. After the first 120 
minutes have elapsed, subjects during confinement may only receive oxycodone 5 mg every 4 
hours, PRN. Following discharge from the hospital, subjects may use 500 mg acetaminophen 
PRN, a maximum of 6 times per day (not to exceed 3 g total dose in 24 hours). Subjects will be 
instructed not to take rescue medication until their pain reaches at least a moderate intensity, and 
to complete an entry in their Pain Assessment Diary prior to taking rescue medication. All post-
discharge rescue medication usage must be recorded in the Rescue Medication Diary.  Subjects’ 
rescue use will be captured on the Rescue Medication eCRF during the Inpatient portion of the 
study and in the Subject Rescue diary after discharge until Day 29. If additional rescue 
medication, other than the study rescue medications, appear on the concomitant medications 
page and can be identified, those medications will also be included in summaries as described 
below. 
The summary will include all rescue taken by subjects regardless of their status (discontinued 
from efficacy or not).   
Total amount of opioids (MEQ) used during the first 96 hours will be summarized overall (0-
96hrs). Table 7-1 will be used to calculate the morphine milligram equivalents (MEQ) for each 
medication. The total opioid consumption for each day for each subject will be calculated as the 
sum of the MEQs of all of the medications taken on that day. For example, if a subject takes 5 
MEQ morphine on Day 1 and Day 2, and 10 MEQ of Oxycodone on Day 2, the total consumption 
for Day 1 is 5 MEQ, and the total consumption for Day 2 is 15 MEQ. Subjects that take no opioids 
on a day will have a total opioid consumption value of zero for that day.  
 
 
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Table 7-1 
Table of Morphine Milligram Equivalents  
(from cdc.gov/drugoverdose/pdf) 
Opioid (Doses in mg/day) 
Conversion Factor 
Codeine 
0.15 
Fentanyl transdermal (in mcg/hr) 
2.4 
Hydrocodone 
1 
Hydromorphone 
4 
Morphine 
1 
Oxycodone 
1.5 
Oxymorphone 
3 
 
Total dose of Oxycodone used during the first 96 hours and the number of doses of Oxycodone 
will both be summarized separately Summaries will be shown both for overall (0-96hrs). Total 
Oxycodone use will also be presented graphically overall and by cohort. 
A by-subject listing presenting the use of rescue medication by time of dosing will be given.
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11. INTERIM ANALYSES AND DATA MONITORING 
There are no planned interim analyses for this study.  Blinded safety meetings were held by the 
SRC after each cohort. 
12. CHANGES TO THE ANALYSES PLANNED IN THE PROTOCOL 
Any deviations from the statistical plan will be described and a justification given in the CSR. 
 
 
 
 
 
 
  
 
 
 
 
 
 
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Electronic Record and Signature Disclosure created on: 8/14/2017 10:16:15 AM
Parties agreed to: Earvin Liang, Jennifer Nezzer, Song Liou