Clinical trial NCT02939326
Conditions: Glabellar Frown Lines (GL)
Sponsor: Bonti, Inc.
Start date: 2016-12-01; Completion date: 2017-07-12
Enrollment: 42 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
To evaluate the safety and efficacy of EB-001 compared to placebo in subjects with glabellar frown lines (GL).

Detailed description:
This study of EB-001 to measure safety and efficacy in GL. Single doses of EB- 001 administered through IM injection into procerus at midline and the medial and lateral corrugators will be assessed in healthy subjects with glabellar frown lines.

Arms: arm 1: Intervention: Drug: Placebo

Single Injection of placebo into five (5) 0.1 mL IM injections into glabellar area. arm 2: Intervention: Drug: EB-001

Single Injection of Low Dose of EB-001 into five (5) 0.1 mL IM Injections into glabellar area arm 3: Intervention: Drug: EB-001, 3X Dose 1

Single Injection of EB-001 into five (5) 0.1 mL IM Injections into glabellar area arm 4: Intervention: Drug: EB-001, 9X Dose 1

Single Injection of EB-001 into five (5) 0.1 mL IM Injections into glabellar area arm 5: Intervention: Drug: EB-001, 12X Dose 1

Single Injection of EB-001 into five (5) 0.1 mL IM Injections into glabellar area arm 6: Intervention: Drug: EB-001, 16X Dose 1

Single Injection of EB-001 into five (5) 0.1 mL IM Injections into glabellar area arm 7: Intervention: Drug: EB-001, 21X Dose 1 Single Injection of EB-001 into five (5) 0.1 mL IM Injections into glabellar area arm 8: Intervention: Drug: EB-001, 28X Dose 1

Single Injection of Highest Dose of EB-001 into five (5) 0.1 mL IM Injections into glabellar area
Interventions: intervention 1: EB-001 injection intervention 2: Placebo injection
Intervention descriptions: intervention 1: None intervention 2: None

Protocol documents:
Prot_SAP_000.pdf: 
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CLINICAL STUDY PROTOCOL 
 
 
A Randomized, Double-Blind, Placebo-Controlled, Ascending Dose Cohort 
Study to Evaluate Safety and Efficacy of a Single Treatment Cycle of EB-001 in 
Subjects with Glabellar Frown Lines 
 
Study Number: EB001-GL201 
 
IND Sponsor: Bonti, Inc. 
 
 
Version Number:  
 
2.0 
Amendment:   
 
1 
Revised Final Date: 
 
18 November 2016 
Original Protocol Date: 
17 October 2016 
 
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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SIGNATURE PAGE 
 
Prepared by: 
 


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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 
 
 
 _______________________  
 _______________________  
 ____________________  
 Investigator Printed Name 
Signature  
Date 
 
 
 _______________________  
 _______________________  
 ____________________  
 Investigator Printed Name 
Signature  
Date 
 
 


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TABLE OF CONTENTS 
SIGNATURE PAGE ....................................................................................................................... 2 
STATEMENT OF COMPLIANCE .................................................................................................... 4 
TABLE OF CONTENTS .................................................................................................................. 5 
LIST OF TABLES ......................................................................................................................... 10 
LIST OF FIGURES ....................................................................................................................... 10 
LIST OF APPENDICES ................................................................................................................ 10 
LIST OF ABBREVIATIONS AND GLOSSARY OF TERMS ............................................................... 11 
PROTOCOL SUMMARY ............................................................................................................. 14 
1 
KEY ROLES .......................................................................................................................... 24 
2 
INTRODUCTION .................................................................................................................. 25 
2.1 
Background Information ................................................................................................ 25 
2.1.1 
Overview of Botulinum Neurotoxins ......................................................................... 25 
2.1.2 
Human Experience of EB-001 .................................................................................... 25 
2.1.3 
Chemistry ................................................................................................................... 26 
2.1.4 
Nonclinical Evaluation of EB-001 ............................................................................... 26 
2.1.4.1 
Toxicology............................................................................................................... 26 
2.1.4.2 
Nonclinical Risk Assessment of EB-001 .................................................................. 27 
2.1.4.3 
in vivo Studies ........................................................................................................ 28 
2.2 
Rationale ........................................................................................................................ 28 
2.2.1 
Study Rationale .......................................................................................................... 28 
2.2.2 
Dose Selection Rationale ........................................................................................... 28 
2.3 
Potential Risks and Benefits .......................................................................................... 29 
2.3.1 
Known Potential Risks ............................................................................................... 29 
2.3.2 
Known Potential Benefits .......................................................................................... 31 
3 
OBJECTIVES AND PURPOSE ................................................................................................ 32 
4 
STUDY DESIGN AND ENDPOINTS ....................................................................................... 33 
4.1 
Description of the Study Design .................................................................................... 33 
4.1.1 
Stopping Criteria ........................................................................................................ 35 
4.1.2 
Follow-up of Subjects Meeting Stopping Criteria ...................................................... 36 
4.2 
Study Endpoints ............................................................................................................. 36 


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4.2.1 
Safety Endpoints ........................................................................................................ 36 
4.2.2 
Primary Efficacy Endpoint .......................................................................................... 37 
4.2.3 
Secondary Efficacy Endpoints .................................................................................... 37 
5 
STUDY ENROLLMENT AND WITHDRAWAL ......................................................................... 38 
5.1 
Participant Inclusion Criteria ......................................................................................... 38 
5.2 
Participant Exclusion Criteria ......................................................................................... 39 
5.3 
Strategies for Recruitment and Retention ..................................................................... 40 
5.4 
Participant Withdrawal or Termination ......................................................................... 40 
5.4.1 
Reasons for Withdrawal or Termination ................................................................... 40 
5.4.2 
Handling of Participant Withdrawals or Termination ............................................... 41 
5.5 
Premature Termination or Suspension of Study ........................................................... 41 
6 
STUDY AGENT .................................................................................................................... 42 
6.1 
Study Agent(s) and Control Description ........................................................................ 42 
6.1.1 
Acquisition ................................................................................................................. 42 
6.1.2 
Formulation, Appearance, Packaging, Labeling, and Shipping.................................. 42 
6.1.3 
Product Storage ......................................................................................................... 42 
6.1.4 
Preparation ................................................................................................................ 42 
6.1.5 
Dosing and Administration ........................................................................................ 43 
6.1.6 
Route of Administration ............................................................................................ 43 
6.1.7 
Starting Dose and Dose Escalation Schedule ............................................................ 43 
6.1.8 
Dose Adjustments/Modification/Delays ................................................................... 43 
6.1.9 
Duration of Treatment ............................................................................................... 43 
6.1.10 
Tracking of Study Kit and Dose .................................................................................. 43 
6.1.11 
Replacement Procedures for Investigational Medicinal Product .............................. 44 
6.2 
Investigational Product Accountability Procedures ....................................................... 44 
7 
STUDY PROCEDURES AND SCHEDULE................................................................................ 45 
7.1 
Study Procedures/Evaluations ....................................................................................... 45 
7.1.1 
Study Specific Procedures ......................................................................................... 45 
7.1.1.1 
Informed Consent .................................................................................................. 46 
7.1.1.2 
Demographics ........................................................................................................ 46 
7.1.1.3 
Assessment of Inclusion/Exclusion Criteria ........................................................... 46 
7.1.1.4 
Medical History ...................................................................................................... 46 
7.1.1.5 
Assessment of Adverse Event ................................................................................ 46 
7.1.1.6 
Height and Weight ................................................................................................. 46 


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7.1.1.7 
Complete Physical and Focused Neurological Examinations ................................. 46 
7.1.1.8 
Mini Physical and Focused Neurological Examinations ......................................... 47 
7.1.1.9 
Prior and Concomitant Medications ...................................................................... 47 
7.1.1.10 
12-Lead ECG ........................................................................................................... 47 
7.1.1.11 
Body Temperature, Respiration Rate, Blood Pressure, and Pulse Rate ................. 47 
7.1.1.12 
Serum Chemistry, Lipids, Hematology ................................................................... 48 
7.1.1.13 
Urinalysis ................................................................................................................ 48 
7.1.1.14 
Immunogenicity Sample Collection ....................................................................... 48 
7.1.1.15 
Screens for HIV and Hepatitis B and C ................................................................... 48 
7.1.1.16 
Screens for Alcohol / Drugs of Abuse .................................................................... 49 
7.1.1.17 
Pregnancy Test ....................................................................................................... 49 
7.1.1.18 
Study Drug Administration .................................................................................... 49 
7.1.1.19 
Standardized Facial Photography ........................................................................... 49 
7.1.1.20 
Facial Wrinkle Scale – Subject Assessment ............................................................ 50 
7.1.1.21 
Facial Wrinkle Scale – Investigator Assessment ..................................................... 50 
7.2 
Laboratory Procedures/Evaluations .............................................................................. 50 
7.2.1 
Clinical Laboratory Evaluations .................................................................................. 50 
7.2.2 
Specimen Preparation, Handling, and Storage .......................................................... 50 
7.2.3 
Specimen Shipment ................................................................................................... 50 
7.2.4 
Volume of Blood Collected ........................................................................................ 50 
7.3 
Study Schedule .............................................................................................................. 51 
7.3.1 
Screening Visit (Days -30 to -1) ................................................................................. 51 
7.3.2 
Baseline Visit (Day 0) ................................................................................................. 51 
7.3.3 
Follow-Up Visits (Days 1, 2, 7, AND 14) ..................................................................... 51 
7.3.4 
End of Study (Day 30) / Early Termination Visit ........................................................ 51 
7.3.5 
Final Follow-Up Visit .................................................................................................. 51 
7.3.6 
Unscheduled Visit ...................................................................................................... 52 
7.3.7 
Schedule of Events Table ........................................................................................... 53 
7.4 
Concomitant Medications and Treatments ................................................................... 55 
7.5 
Prohibited Medications, Treatments, and Procedures .................................................. 55 
7.6 
Subject Restriction ......................................................................................................... 55 
8 
ASSESSMENT OF SAFETY .................................................................................................... 57 
8.1 
Specification of Safety Parameters ................................................................................ 57 
8.1.1 
Definition of Adverse Events (AE) .............................................................................. 57 
8.1.2 
Definition of Serious Adverse Events (SAE) ............................................................... 58 


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8.1.2.1 
Elective Procedures, and Surgeries ........................................................................ 59 
8.1.3 
Definition of Unanticipated Problems (UP) ............................................................... 59 
8.2 
Classification of an Adverse Event ................................................................................. 60 
8.2.1 
Severity of Event ........................................................................................................ 60 
8.2.2 
Relationship to Study Agent ...................................................................................... 60 
8.2.3 
Expectedness ............................................................................................................. 61 
8.3 
Time Period and Frequency for Event Assessment and Follow-up ............................... 61 
8.4 
Reporting Procedures .................................................................................................... 62 
8.5 
Adverse Event Reporting ............................................................................................... 62 
8.5.1 
Serious Adverse Event Reporting .............................................................................. 63 
8.5.2 
Reporting of Pregnancy ............................................................................................. 64 
8.6 
Study Halting Rules ........................................................................................................ 65 
8.7 
Safety Oversight ............................................................................................................. 65 
9 
CLINICAL MONITORING AND COMPLIANCE ...................................................................... 66 
10 STATISTICAL CONSIDERATIONS .......................................................................................... 67 
10.1 Statistical and Analytical Plans ...................................................................................... 67 
10.2 Statistical Hypotheses .................................................................................................... 67 
10.3 Analysis Datasets ........................................................................................................... 67 
10.4 Description of Statistical Methods ................................................................................ 67 
10.4.1 
General Approach ...................................................................................................... 67 
10.4.2 
Analysis of the Primary Efficacy Endpoint(s) ............................................................. 67 
10.4.3 
Analysis of the Secondary Endpoint(s) ...................................................................... 68 
10.4.4 
Safety Analyses .......................................................................................................... 68 
10.4.4.1 
Demographics and Baseline Characteristics .......................................................... 68 
10.4.4.2 
Prior and Concomitant Medications ...................................................................... 68 
10.4.4.3 
Completion of the Study and Withdrawals ........................................................... 68 
10.4.4.4 
Tolerability Analysis ............................................................................................... 68 
10.4.4.5 
Adverse Events ....................................................................................................... 68 
10.4.4.6 
Clinical Laboratory Tests ........................................................................................ 69 
10.4.4.7 
Vital Signs............................................................................................................... 69 
10.4.4.8 
Electrocardiograms ................................................................................................ 70 
10.4.4.9 
Physical and Focused Neurological Examinations ................................................. 70 
10.4.4.10 Immunogenicity ..................................................................................................... 71 
10.4.4.11 Urine Drug Test ...................................................................................................... 71 


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10.4.4.12 Pregnancy Test ....................................................................................................... 71 
10.4.5 
Planned Interim Analyses .......................................................................................... 71 
10.4.6 
Exploratory Analyses ................................................................................................. 71 
10.5 Sample Size .................................................................................................................... 71 
10.6 Measures to Minimize Bias ............................................................................................ 72 
10.6.1 
Enrollment/ Randomization/ Blinding Procedures .................................................... 72 
10.6.1.1 
Subject Numbering ................................................................................................ 72 
10.6.2 
Evaluation of Success of Blinding .............................................................................. 73 
10.6.2.1 
Blinding at the Study Site ....................................................................................... 73 
10.6.2.2 
Blinding of Sponsor Personnel ............................................................................... 73 
10.6.3 
Breaking the Study Blind/Participant Code ............................................................... 73 
11 SOURCE DOCUMENTS AND ACCESS TO SOURCE DATA/DOCUMENTS .............................. 75 
12 QUALITY ASSURANCE AND QUALITY CONTROL ................................................................. 76 
13 ETHICS/PROTECTION OF HUMAN SUBJECTS ..................................................................... 77 
13.1 Ethical Standard ............................................................................................................. 77 
13.2 Institutional Review Board ............................................................................................ 77 
13.3 Informed Consent Process ............................................................................................. 77 
13.4 Participant and Data Confidentiality ............................................................................. 77 
13.4.1 
Research Use of Stored Human Samples or Data ...................................................... 78 
13.5 Future Use of Stored Specimens ................................................................................... 78 
13.6 Protocol Amendments and Study Termination ............................................................. 78 
14 DATA HANDLING AND RECORD KEEPING ........................................................................... 80 
14.1 Data Collection and Management Responsibilities....................................................... 80 
14.2 Study Records Retention and Availability ..................................................................... 80 
14.3 Protocol Deviations ....................................................................................................... 81 
14.4 Publication and Data Sharing Policy .............................................................................. 81 
15 CONFLICT OF INTEREST POLICY ......................................................................................... 82 
16 LITERATURE REFERENCES .................................................................................................. 83 
17 APPENDIX ........................................................................................................................... 85 
 
 


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LIST OF TABLES 
Table 1  
Likely symptoms from spread of botulinum toxin ........................................... 30 
Table 2 
Dose Escalation Scheme .................................................................................. 34 
Table 3  
Toxicity Criteria ................................................................................................ 36 
Table 4  
Total Blood Volume Collected for Each Subject ............................................... 51 
Table 5  
Schedule of Study Events ................................................................................. 53 
Table 6  
Criteria for Clinically Notable Vital Sign Abnormalities ................................... 69 
Table 7  
Criteria for Clinically Notable ECG Interval Abnormalities ............................... 70 
Table 8  
Probability of Detecting Adverse Events that Occur at Various Frequencies .. 72 
 
LIST OF FIGURES 
Figure 1 
Injection Sites ................................................................................................... 34 
Figure 2 
Schematic of Dose Escalation .......................................................................... 35 
  
LIST OF APPENDICES 
Appendix 1 
Focused Neurological Examination Sheet ........................................................ 85 
Appendix 2 
FWS Assessment Sheet .................................................................................... 91 
Appendix 3 
Clinical Laboratory Test .................................................................................... 93 
 


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LIST OF ABBREVIATIONS AND GLOSSARY OF TERMS 
Term 
Definition 
AE 
adverse event 
ALT (SGPT) 
alanine aminotransferase (= serum glutamic pyruvic transaminase) 
AST (SGOT) 
aspartate aminotransferase (= serum glutamic oxaloacetic 
transaminase) 
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 
CTCAE 
Common Terminology Criteria for Adverse Events 
DAS 
digital abduction score 
DRT 
Data Review Team 
EB-001 
botulinum neurotoxin serotype E drug product 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
ED50 
effective dose to product 50% DAS effect 
EDC 
electronic data capture 
EOS 
end of study 
ET 
early termination 
F-U 
follow up 
FDA 
Food and Drug Administration 
FIH 
first-in-human 
FWS 
facial wrinkle scale 
GCP 
Good Clinical Practice 
GGT 
γ glutamyl transferase 
GL 
glabellar frown Lines 
GLP 
Good Laboratory Practices 


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Term 
Definition 
GMP 
Good Manufacturing Practices 
HBsAg 
hepatitis B surface antigen 
HC 
heavy chain 
HDL 
high density lipoprotein 
HED 
human equivalent dose 
HEENT 
head, eye, ear, 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 
IVRS 
interactive voice response system 
IWRS 
interactive web response system 
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 
mL 
milliliter 
mouse LD50 
lethal dose to 50% of mice after intraperitoneal injection 
MRSD 
maximum recommended starting dose 
msec 
milliseconds 
NA 
not applicable 
ng 
nano gram  
NOAEL 
no observable adverse effects limit 


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Term 
Definition 
OHRP 
Office for Human Research Protections 
PAD 
pharmacologically active dose 
PCV 
packed cell volume 
PI 
Principal Investigator 
PR interval 
time between the onset of atrial depolarization and the onset of 
ventricular depolarization 
PRN 
as-needed 
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 
SNAP 
synaptosomal-associated protein 
SOT 
spread of toxin 
SUSAR 
suspected unexpected serious adverse reactions 
RR interval 
time elapsing between two consecutive R waves in the 
electrocardiogram. It is used to assess the ventricular rate. 
TCA 
trichloroacetic Acid 
TEAE 
treatment emergent adverse event 
UP 
unanticipated problem 
US 
United States 
WBC 
white blood cell (Leukocyte) 
 
 


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 PROTOCOL SUMMARY 
 
Study Number: 
EB001-GL201 
 
Study Title: 
A Randomized, Double-Blind, Placebo-Controlled, Ascending Dose Cohort Study to Evaluate 
Safety and Efficacy of a Single Treatment Cycle of EB-001 in Subjects with Glabellar Frown 
Lines 
 
Investigational Drug Product: 
EB-001 (Botulinum Neurotoxin Serotype E, BoNT/E) for injection. 
 
Study Objectives: 
To evaluate the safety and efficacy of EB-001 compared to placebo in subjects with glabellar 
frown lines (GL). 
 
Phase of Trial: 
Phase 2a 
 
Clinical Hypothesis: 
Safety: A single treatment cycle of EB-001 Intramuscular (IM) injections into the glabellar 
muscles (procerus and bilateral corrugator muscles) has an acceptable safety, 
immunogenicity, and tolerability profile at the tested dose range.  Immunogenicity testing 
will be performed once methods have been developed.  
 
Efficacy: A single treatment cycle of EB-001 IM injections, at one or more of the tested 
doses, is more effective than placebo in the treatment of GL assessed using the Facial 
Wrinkle Scale (FWS). 
 
Study Population: 
Males and Females 18-60 years old, with moderate to severe GL at maximum frown using 
the FWS. 
 
Outcome Measures: 
Safety Measures:  
• Incidence and severity of treatment emergent adverse events (TEAEs) and serious 
adverse events (SAEs) 
• Focused neurologic examination for potential spread of toxin (SOT) 
• Incidence of abnormal findings in laboratory tests, electrocardiogram (ECG), physical 
exam, and vital signs (pulse rate, respiratory rate, and blood pressure) 
• Pregnancy test for women of childbearing potential 
 


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Efficacy Measures: 
Primary Efficacy Measures: 
• Investigator’s assessment of GL severity at maximum frown using the FWS. The FWS 
is a four-point scale that indicates severity of GL as follows: 0 = none, 1 = mild, 2 = 
moderate, or 3 = severe.  
 
 
  
  
 
Study Design: 
This will be the first-in-human (FIH), randomized, double-blind, placebo-controlled, 
ascending dose cohort study of EB-001.   
 
A total of 7 ascending dose cohorts are planned for GL injections or up to 9 cohorts if 2 
additional cohorts are evaluated. Each dose cohort will enroll a total of 6 subjects 
randomized to receive either EB-001 or placebo in a ratio of 5 (active): 1 (placebo). 
 
Duration: 
Expected duration is approximately 6 weeks for each subject from the day of study 
treatment to the follow-up visit, and approximately 10 weeks from signing ICF to the follow-
up exit. 
 
Inclusion Criteria: 
In order to be eligible to participate in this study, an individual must meet ALL of the 
following criteria: 
1. Signed and dated IRB-approved informed consent form (ICF). 
2. Men or women between the ages of 18 and 60, inclusive. 
3. Subjects in good health as determined by medical history, physical and focused 
neurological examinations, clinical laboratory studies, electrocardiograms (ECGs), 
vital signs, and Investigator’s judgement. 
4. Presence of bilaterally symmetrical GL of moderate to severe rating at maximum 
frown, as measured using FWS by both the Investigator and subject prior to study 
treatment.  
5. Subjects with sufficient visual acuity without the use of eyeglasses (contact lens use 
acceptable) to accurately assess their facial wrinkles as determined by Investigator’s 
judgement. 
6. Women of child bearing potential must not be pregnant, lactating, or planning to 
become pregnant during the study.  
7. Women of non-childbearing potential must be either postmenopausal (at least 12 
consecutive months of amenorrhea) or surgically sterile (e.g., tubal ligation, 
hysterectomy, etc.). 


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8. Women of childbearing potential agreeing to use dual methods of contraception 
from the day of dosing until 3 months afterwards.  Female subjects using oral 
contraception must have initiated treatment at least 2 months prior to the day of 
dosing.   
9. Male subjects 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. 
10. Willing and able to complete protocol requirements and instructions, which include 
completion of all required visits. 
 
Exclusion Criteria: 
An individual who meets ANY of the following criteria will be excluded from participation in 
this study: 
1. Any condition that precludes a subject’s ability to comply with study requirements, 
including completion of the study visits or inability to read, understand, and/or self-
assess GL severity using FWS. 
2. Any uncontrolled systemic disease or other medical condition. 
3. Any medical condition that may put the subject at increased risk with exposure to 
botulinum toxin of any serotype, including diagnosed myasthenia gravis, Eaton-
Lambert syndrome, amyotrophic lateral sclerosis, or any other condition that might 
interfere with neuromuscular function. 
4. Current or previous botulinum toxin treatment of any serotype. 
5. Anticipated need for treatment with botulinum toxin of any serotype for any reason 
during the study (other than study treatment). 
6. Known immunization or hypersensitivity to any botulinum toxin serotype. 
7. Known allergy or sensitivity to any of the components of the study treatments, or 
any materials used in the study procedures. 
8. Any of the following procedures or treatments occurring within the specified period 
prior to screening: 
o 3 months: Non-ablative resurfacing laser or light treatment, microdermabrasion, 
or superficial peels. 
o 6 months: Any facial cosmetic procedure with medium depth to deep facial 
chemical peels (e.g., trichloroacetic acid [TCA] and phenol), or mid facial or 
periorbital laser skin resurfacing. 
o 6 months: On topical retinoid therapy and/or topical hormone cream applied to 
the face, who have not been on a consistent dose regimen and are unable to 
maintain the same regimen for the study. 
o 12 months: Mid-facial or periorbital treatment with non-permanent soft tissue 
fillers. 
o 12 months: On oral retinoid therapy. 
9. Prior periorbital surgery, facial lift (full face or mid face), brow lift, or related 
procedures (e.g., eyelid [blepharoplasty] and/or eyebrow surgery). 
10. Prior mid face or periorbital treatment with permanent soft tissue fillers, synthetic 
implantation (e.g., Gore-Tex®), and/or autologous fat transplantation. 


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11. Marked facial asymmetry, dermatochalasis, deep dermal scarring, and/or excessively 
thick sebaceous skin. 
12. The inability to substantially lessen facial rhytides (fixed lines) even by physically 
spreading them apart, as determined by the Investigator. 
13. Permanent make-up that would interfere with the assessment of facial wrinkles. 
14. Subjects who, in the Investigator’s opinion, are unable or unwilling to maintain their 
standardized skin care regimen throughout the study period. 
15. Any eyebrow or eyelid ptosis at baseline as determined by the Investigator. 
16. Infection or skin disorder at the injection sites. 
17. History of facial nerve palsy. 
18. Recent history (within 6 months of screening) of alcohol or drug abuse based on the 
Investigator’s judgement. 
19. Anticipated need for surgery or overnight hospitalization during the study. 
20. 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. 
 
Study Drug: 
 
 
 
Placebo: 
Sterile solution for injection with
 
 
Dosage: 
The total dose will be the specified amount of EB-001, or placebo, divided into 5 injections; 1 
injection into procerus at midline and a single injection into each of the medial and lateral 
corrugators bilaterally (Figure S-1). Each subject will always receive 5 injections and the 
volume injected per site will be 0.1 mL. The spacing of injections into the lateral corrugators 
should be at or about 1 centimeter above the supraorbital ridge, which is known to minimize 
potential ptosis. 
 
Figure S–1 
Injection Sites 
 
 


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Starting Dose and Dose Escalation: 
Dose escalation scheme is shown in Table S-1 below. Additional doses (cohorts) may be 
explored as defined below in Flexibility in Dose Adjustment.   
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 


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Flexibility in Dose Adjustment: 
If an intolerable dose is identified, a lower dose may be evaluated.  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. 
 
Any dose cohort below the intolerable dose cohort may be repeated, if requested by the 
DRT, to better evaluate any finding at that dose level. 
 
All dose escalation/adjustments or additional cohorts will be determined by the DRT up to a 
total of 9 dose cohorts for up to a total of 54 subjects. 
 
Screening: 
Written ICF, demographics, inclusion/exclusion criteria, medical history, physical and focused 
neurological examinations, height/weight, prior and concomitant medications, triplicate 
ECG, 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, and serum pregnancy test.  
 
Safety Assessments: 
Adverse events, physical and focused neurologic examinations, prior and concomitant 
medications, triplicate ECG, vital signs, clinical laboratory tests, medical history, and 
serum/urine pregnancy test. 
 
Efficacy Assessments 
Investigator’s and subject’s assessment of the FWS with Photonumeric Guide at maximum 
frown and at rest. 
 
Other Assessments 
Standardized Facial Photography. 
 
General Statistical Considerations: 
The planned sample size will be approximately 42 subjects (35 for EB-001 and 7 for placebo) 
if all 7 cohorts are evaluated, or up to 54 subjects if additional 2 cohorts are evaluated.  All 


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statistical analysis will be descriptive summary statistics. The placebo subjects will be 
pooled. The probabilities of observing at least 1 event detecting adverse events with given 
true event rate are shown in Table S-2: 
 
Table S–2 
Probability of Detecting Adverse Events that Occur at Various Frequencies  
True Event 
Rate 
Probability of Observing at Least 
1 Event with 5 Completed Subjects 
Probability of Observing at Least 
1 Event with 35 Subjects 
0.01 
4.9% 
29.7% 
0.1 
41.0% 
97.5% 
0.2 
67.2% 
>99% 
0.5 
96.9% 
>99% 
 
Demographic and baseline characteristics will be summarized.  Safety will be assessed by 
summarizing the incidence of all adverse events, TEAEs, and serious adverse events. Other 
safety parameters (clinical laboratory parameters, vital signs, and ECG measures), including 
mean absolute change from baseline, will be summarized by treatment group.  Efficacy will 
be assessed by summarizing the change from baseline of Investigator’s and subject’s 
assessment of GL severity at maximum frown and at rest using the FWS. 
 


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1 KEY ROLES 


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2 INTRODUCTION 
2.1 Background Information 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
   
 
 
 
 
 
 
 


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BoNT serotype E (BoNT/E, EB-001) has been previously studied in human subjects with 
  
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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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potency of EB-001 drug product is 22 Units per ng and the recommended dosage for the 
 
 
 
  
 
 
 
 
  
 
  
 
 
 
   
 
 
 
2.2 Rationale 
2.2.1 Study Rationale 
This will be the FIH study of EB-001 to measure safety and efficacy in GL. Single doses of EB-
001 administered through IM injection into procerus at midline and the medial and lateral 
corrugators will be assessed in healthy subjects with glabellar frown lines.  
 
A total of 7 ascending dose cohorts are planned, or up to 9 cohorts if 2 additional cohorts 
are evaluated.  Each dose cohort will enroll a total of 6 subjects randomized to receive either 
EB-001 or placebo in a ratio of 5 (active): 1 (placebo).  
 
 
 


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Table 1  
Likely symptoms from spread of botulinum toxin 
Body and Limbs Category 
• 
Decreased muscle tone 
• 
Loss of muscle function 
• 
Loss of muscle tone 
• 
Weakened reflexes 
• 
Lack of reflexes 
• 
Muscular weakness 
• 
Muscle weakness of all four limbs 
• 
Partial loss of voluntary movement 
• 
Partial paralysis of one limb 
• 
Partial paralysis of one side of the 
body 
• 
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 
• 
Blurred vision 
• 
Double vision 
• 
Drooping of upper eyelid 
• 
Eyelid function irregularity 
• 
Inability to focus or maintain a clear 
image 
• 
Partial loss of eye movement  
• 
Partial loss of eye muscle movement 
(eyelid)  
• 
Partial loss of eye muscle movement 
(vertical glaze)  
Face Category 
• 
Loss of facial movement 
• 
Loss of feeling in face 
• 
Loss of movement in face 
• 
Partial loss of feeling in face 
Heart and Lungs Category 
• 
Difficulty breathing 
• 
Inflammation of the lungs 
• 
Shortness of breath 
• 
Slowed breathing 
• 
Slow heart rate 


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Mouth Category 
• 
Difficulty speaking 
• 
Difficulty swallowing 
• 
Difficulty with motor skills (slurred 
speech, difficulty chewing and 
swallowing) 
• 
Dry mouth 
• 
Inability to move vocal cords 
• 
Partial loss of facial motor functions 
(biting and chewing) 
• 
Partial loss of tongue movement 
• 
Speech impediment 
• 
Stuttering 
• 
Weakness of vocal cords 
 
Stomach and Intestine Category 
• 
Bowel blockage 
• 
Constipation 
• 
Unable to urinate completely 
 
 
Another risk is the possibility of an allergic reactions to drugs and to product ingredients. If a 
subject has a very bad 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. 
 
The events of serious allergic reactions have been rare in the case of botulinum neurotoxin 
serotype A (for example, 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 include aesthetic improvement in 
appearance by reduction of GL at maximum frown and at rest.  
 


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3 OBJECTIVES AND PURPOSE 
This will be the FIH study of EB-001 to evaluate safety and efficacy in GL.  
 
The safety objective is whether a single treatment cycle of EB-001 IM injections into the 
glabellar muscles (procerus and bilateral corrugator muscles) has an acceptable safety, and 
tolerability profile at the tested dose range.  
 
The efficacy objection is whether a single treatment cycle of EB-001 IM injections, at one or 
more of the tested doses, is more effective than placebo in the treatment of GL assessed 
using the FWS. 
 


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4 STUDY DESIGN AND ENDPOINTS 
4.1 Description of the Study Design 
This will be the FIH, multicenter, ascending dose cohort, randomized, double-blind, placebo-
controlled, single treatment cycle study of EB-001 IM injections in subjects with moderate to 
severe GL at maximum frown using Facial Wrinkle Scale (FWS).  Expected duration is 
approximately 6 weeks for each subject from the day of study treatment to the follow-up 
visit, and approximately 10 weeks from signing informed consent form (ICF) to the follow-up 
exit. 
 
 
 
. 
 
Placebo: 
Sterile solution for injection 
 
 
 
Dosage: 
Subjects in each cohort will be randomized to receive either EB-001 or placebo, and each 
cohort will receive a different dose level of EB-001, which will generally be at a higher dose 
than the previous cohort, although dose modifications may be made depending on the 
safety and tolerability.   
 
The total dose will be the specified amount of EB-001, or placebo, divided into 5 injections; 1 
injection into procerus at midline and a single injection into each of the medial and lateral 
corrugators bilaterally (Figure 1).  Each subject will always receive 5 injections and the 
volume injected per site will be 0.1 mL.  The spacing of injections into the lateral corrugators 
should be at or about 1 centimeter above the supraorbital ridge, which is known to minimize 
potential ptosis.  
 
There is no diet or water restriction throughout the study. 
 


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Figure 1 
Injection Sites 
 


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4.1.1 Stopping Criteria 
When there are 2 or more subjects experiencing intolerable treatment emergent adverse 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Table 3  
Toxicity Criteria 
TEAE 
Definition1 
Serious adverse event 
See Section 8.1.2 
Related to spread of toxin2 
CTCAE ≥Grade 2 
Related to Laboratory and ECG parameters3 
CTCAE ≥Grade 2 
All others (other than the SOT or laboratory and ECG parameters) 
CTCAE >Grade 2 
Unspecified 
If considered appropriate by the 
Medical Monitor and Investigator 
 1 Unless considered to be unrelated to study medication 
 2 FDA Draft Guidance, Upper Facial Lines: Developing Botulinum Toxin Drug Products (FDA 2014). 
 3 To be confirmed by a repeat test 
Flexibility in Dose Adjustment: 
If an intolerable dose is identified (based on one of the above 3 criteria), a lower dose may 
be evaluated.  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. 
 
Any dose cohort below the intolerable dose cohort may be repeated, if requested by the 
DRT, to better evaluate any finding at that dose level. 
 
All dose escalation/adjustments or additional cohorts will be determined by the DRT up to a 
total of 9 dose cohorts for up to a total of 54 subjects. 
 
4.1.2 Follow-up of Subjects Meeting Stopping Criteria 
Subjects with any of the criteria in Table 3 will be monitored carefully, which may include the 
following (to be agreed upon by the Investigator and the Medical Monitor): 
• Additional clinical laboratory tests and/or other investigations. 
• Additional outpatient visits. 
• Extended duration of follow-up. 
• Obtaining a specialist’s opinion. 
 
4.2 Study Endpoints 
4.2.1 Safety Endpoints 
• Incidence and severity of TEAEs and serious adverse events (SAEs). 
• Focused neurologic examination for potential SOT (See Appendix 1 for examination 
sheet). 
• Incidence of abnormal findings in laboratory tests, electrocardiogram (ECG), physical 
examination, and vital signs (pulse rate, respiratory rate, and blood pressure). 
• Serum/urine pregnancy test for women of childbearing potential. 


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4.2.2 Primary Efficacy Endpoint 
• The primary endpoint is the Investigator’s assessment of GL severity at maximum 
frown using the FWS.  
 
The FWS is a four-point scale that indicates severity of GL as follows: 0 = none, 1 = mild, 2 = 
moderate, or 3 = severe (see Appendix 2 for sample FWS assessment sheet). 
 
4.2.3 Secondary Efficacy Endpoints 
• Investigator’s assessment of GL severity at rest using the FWS. 
• Subject’s assessment of GL severity at maximum frown using the FWS. 
• Subject’s assessment of GL severity at rest using the FWS. 
 


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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.   
 
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. Signed and dated IRB-approved informed consent form (ICF). 
2. Men or women between the ages of 18 and 60, inclusive. 
3. Subjects in good health as determined by medical history, physical and focused 
neurological examinations, clinical laboratory studies, electrocardiograms (ECGs), 
vital signs, and Investigator’s judgement. 
4. Presence of bilaterally symmetrical GL of moderate to severe rating at maximum 
frown, as measured using FWS by both the Investigator and subject prior to study 
treatment.  
5. Subjects with sufficient visual acuity without the use of eyeglasses (contact lens use 
acceptable) to accurately assess their facial wrinkles as determined by the 
Investigator’s judgement. 
6. Women of child bearing potential must not be pregnant, lactating, or planning to 
become pregnant during the study. 
7. Women of non-childbearing potential must be either postmenopausal (at least 12 
consecutive months of amenorrhea) or surgically sterile (e.g., tubal ligation, 
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8. Women of childbearing potential agreeing to use dual methods of contraception 
from the day of dosing until 3 months afterwards.  Female subjects using oral 
contraception must have initiated treatment at least 2 months prior to the day of 
dosing.   
9. Male subjects 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. 
10. Willing and able to complete protocol requirements and instructions, which includes 
completion of all required visits. 
 
5.2 Participant Exclusion Criteria 
An individual who meets ANY of the following criteria will be excluded from participation in 
this study: 
1. Any condition that precludes a subject’s ability to comply with study requirements, 
including completion of the study visits or inability to read, understand, and/or self-
assess GL severity using FWS. 
2. Any uncontrolled systemic disease or other medical condition. 
3. Any medical condition that may put the subject at increased risk with exposure to 
botulinum toxin of any serotype, including diagnosed myasthenia gravis, Eaton-
Lambert syndrome, amyotrophic lateral sclerosis, or any other condition that might 
interfere with neuromuscular function. 
4. Current or previous botulinum toxin treatment of any serotype. 
5. Anticipated need for treatment with botulinum toxin of any serotype for any reason 
during the study (other than study treatment). 
6. Known immunization or hypersensitivity to any botulinum toxin serotype. 
7. Known allergy or sensitivity to any of the components of the study treatments, or 
any materials used in the study procedures. 
8. Any of the following procedures or treatments occurring within the specified period 
prior to screening: 
o 3 months: Non-ablative resurfacing laser or light treatment, microdermabrasion, 
or superficial peels. 
o 6 months: Any facial cosmetic procedure with medium depth to deep facial 
chemical peels (e.g., trichloroacetic acid [TCA] and phenol), or mid facial or 
periorbital laser skin resurfacing. 
o 6 months: On topical retinoid therapy and/or topical hormone cream applied to 
the face, who have not been on a consistent dose regimen and are unable to 
maintain the same regimen for the study. 
o 12 months: Mid-facial or periorbital treatment with non-permanent soft tissue 
fillers. 
o 12 months: On oral retinoid therapy. 
9. Prior periorbital surgery, facial lift (full face or mid face), brow lift, or related 
procedures (e.g., eyelid [blepharoplasty] and/or eyebrow surgery). 


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10. Prior mid face or periorbital treatment with permanent soft tissue fillers, synthetic 
implantation (e.g., Gore-Tex®), and/or autologous fat transplantation. 
11. Marked facial asymmetry, dermatochalasis, deep dermal scarring, and/or excessively 
thick sebaceous skin. 
12. The inability to substantially lessen facial rhytides (fixed lines) even by physically 
spreading them apart, as determined by the Investigator. 
13. Permanent make-up that would interfere with the assessment of facial wrinkles. 
14. Subjects who, in the Investigator’s opinion, are unable or unwilling to maintain their 
standardized skin care regimen throughout the study period. 
15. Any eyebrow or eyelid ptosis at baseline as determined by the Investigator. 
16. Infection or skin disorder at the injection sites. 
17. History of facial nerve palsy. 
18. Recent history (within 6 months of screening) of alcohol or drug abuse based on the 
Investigator’s judgement. 
19. Anticipated need for surgery or overnight hospitalization during the study. 
20. 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. 
 
5.3 Strategies for Recruitment and Retention 
Sufficient subjects will be screened to allow for approximately 42 eligible subjects to be 
randomized at 2 US-based investigational sites. 
 
Subjects will be mainly recruited via referrals. 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 informed 
consent will be admitted. Preliminarily 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.  


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• The participant meets an exclusion criterion (either newly developed or not 
previously recognized) that precludes further study participation.  
• Noncompliance with the protocol. 
• At the discretion of the Investigator or Sponsor for any reason. 
 
5.4.2 Handling of Participant Withdrawals 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 from the study may be replaced unless it is due to one of the 
toxicity criteria in Table 3, in which situation subjects will not be replaced. 
 
5.5 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. 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. 
 
Study may resume once concerns about safety, protocol compliance, and/or data quality are 
addressed and satisfy the Sponsor, IRB and/or FDA. 
 


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6 STUDY AGENT 
 
 
 
  
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 


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6.1.5 Dosing and Administration 
See Section 4.1. 
 
6.1.6 Route of Administration 
Intramuscular 
 
6.1.7 Starting Dose and Dose Escalation Schedule 
See Section 4.1. 
 
6.1.8 Dose Adjustments/Modification/Delays 
If an intolerable dose is identified, a lower dose may be evaluated.  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. 
 
Any dose cohort below the intolerable dose cohort may be repeated, if requested by the 
DRT, to better evaluate any finding at that dose level. 
 
All dose escalation/adjustments or additional cohorts will be determined by the DRT up to a 
total of 9 dose cohorts for up to a total of 54 subjects. 
 
6.1.9 Duration of Treatment 
Expected duration is approximately 6 weeks for each subject from the day of study 
treatment to the follow-up visit, and approximately 10 weeks from signing ICF to the follow-
up exit. 
 
The entire study duration is expected to take approximately seven months from the first visit 
of the first subject (screening) to the last visit of the last subject. 
 
6.1.10 Tracking of Study Kit and Dose 
The Investigator will keep a record of the dates study drug kits received, the dose dispensed 
to each study subject from each kit.  After dose is administered to the subject, the dispenser 
will collect and place the remaining vials back to the kit, and reseal it until CRA conducts 
final drug accountability which will be verified and reconciled on the Study Drug Kit 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 
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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). 
 
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 Kit Log will be provided for the accounting of study drug.  Study Drug Kit 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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7 STUDY PROCEDURES AND SCHEDULE 
7.1 Study Procedures/Evaluations 
The principal Investigator and Sponsor must agree upon the format and content of the ICF 
before it is submitted to the IRB for approval.  Written informed consent must be obtained 
from each subject prior to any study-related activities being conducted.  The Investigator 
must retain all original signed and personally dated ICFs (together with any subsequent IRB-
approved amended versions) in the subject’s file.  A copy of the original signed and dated ICF 
(and any amendments) must be given to the subject.   
 
Subjects will be informed of findings (including AEs) from earlier cohorts if it is considered 
these could potentially affect the subject’s willingness to participate or continue in the 
study.  Depending on the nature, severity, and seriousness of these AEs, the ICF may be 
amended. 
 
7.1.1 Study Specific Procedures 
• Informed Consent 
• Demographics 
• Assessment of inclusion/exclusion criteria 
• Medical history 
• Assessment of adverse event 
• Height and weight 
• Complete physical and focused neurological examinations 
• Mini Physical and focused neurological examinations 
• Prior and concomitant medications 
• 12-lead ECG 
• Body temperature, respiration rate, blood pressure, and pulse rate 
• Serum chemistry, Lipids, Hematology 
• Urinalysis 
• Immunogenicity sample collection  
• Screens for HIV and hepatitis B and C 
• Screens for alcohol / drugs of abuse 
• Serum/urine pregnancy test 
• Study drug administration 
• Standardized Facial Photography  
• Facial Wrinkle Scale – Subject Assessment 
• Facial Wrinkle Scale – Investigator Assessment 
 


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7.1.1.1 Informed Consent 
At the Screening Visit, prior to any procedures are performed, the site staff will obtain the 
signed ICF from each participant. 
 
7.1.1.2 Demographics 
At the Screening Visit, the site staff will be responsible for collecting the age, sex, ethnicity, 
and race. 
 
7.1.1.3 Assessment of Inclusion/Exclusion Criteria 
At the Screening and the Baseline (prior to dosing) Visits, the site staff will be responsible 
for reviewing the inclusion and exclusion criteria to determine the subject’s eligibility for the 
study.   
 
7.1.1.4 Medical History 
At the Screening Visit, medical history of the subject will be conducted.  Any untoward 
medical occurrence that occurs after signing ICF is considered AE. 
 
7.1.1.5 Assessment of Adverse Event 
Adverse events will be recorded beginning after signing the ICF until completion of the study 
until the final follow-up visit (Day 42), and will be evaluated by the Investigator for severity 
(using CTCAE version 4.03 criteria (CTCAE 2010)), seriousness, and attributability to study 
medication.  Further details on AEs, including definitions, elicitation, and reporting are 
provided in Section 8. 
 
7.1.1.6 Height and Weight 
At the Screening Visit, subject height will be recorded.  Height (cm) measured from the 
Screen Visit will be carried forward to Day 0.  At the Screening and Baseline (prior to dosing) 
Visits, subject weight (kg, in indoor clothing, but without shoes) will be measured.    
 
7.1.1.7 Complete Physical and Focused Neurological Examinations 
At the Screening and the Baseline (prior to dosing) Visits, complete physical examinations 
(including but not limited to: dermatologic, head, eye, ear, nose, throat (HEENT), respiratory, 
cardiovascular, abdomen, lymph nodes, musculoskeletal) will be performed.  Focused 
neurological examination will assess potential SOT per instructions in the Appendix 1. 
 


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7.1.1.8 Mini Physical and Focused Neurological Examinations 
At Days 1, 2, 7, 14, 30 (EOS/ET), and 42 Visits, mini physical examination that is symptom-
oriented will be performed.  Focused neurological examination will assess potential SOT per 
instructions in the Appendix 1. 
 
7.1.1.9 Prior and Concomitant Medications 
At the Screening Visit, the Baseline Visit, and at all subsequent scheduled and unscheduled 
clinic visits, prior and concomitant medications will be assessed. 
 
Medications taken within 30 days prior to the screening visit and up to the study drug 
administration will be considered to be prior medications.  Concomitant medication is 
defined as any medication that is taken after the study drug administration (Day 0).  Any use 
of prior and concomitant medications will be recorded on the Concomitant Medications 
electronic Case Report Form (eCRF).  During the study, initiation of or change in concomitant 
medications to treat an AE must also be recorded on an AE eCRF for that AE. 
 
7.1.1.10 12-Lead ECG 
At the Screening Visit, Day 2 Visit, and Day 30 (EOS/ET) Visit, a standard 12-lead ECG will be 
recorded in the supine position after at least 5 minutes rest.  All ECG measures will be 
performed in triplicate, with each consecutive measure approximately 1 minute apart.  In 
addition, where applicable, ECGs will be performed prior to blood draws. 
 
The definitive ECG assessments will be conducted by a central ECG-reading facility.  The 
assessment of the ECG by the central ECG-reading facility will include heart rate (HR), ECG 
intervals/durations (RR interval, PR interval, QRS duration, QT interval, and QTc interval 
using Fridericia’s and Bazett’s corrections [QTcF and QTcB intervals, respectively; see List of 
Abbreviations and Glossary of Terms), and assessments of the waveform.  The tracings may 
be reviewed and reported both locally and by a blinded central reader.  In the event that the 
clinical study site and the central reader disagree on the interpretation of the results, the 
central reader’s interpretation will be considered final.  The centrally reported ECG results 
will be used in the data analyses. 
 
7.1.1.11 Body Temperature, Respiration Rate, Blood Pressure, and Pulse Rate 
At the Screening Visit, Baseline Visit (Day 0), and at all subsequent scheduled clinic visits till 
Day 30 (EOS/ET) visit, vital signs including body temperature, respiration rate, blood 
pressure, and pulse rate will be recorded.  In addition, where applicable, vital sign data will 
be collected prior to blood draws. 
 


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Body temperature taken either orally or aurally will be the same throughout the study.  
Respiration rate will be taken at a quiet resting state prior to blood pressure (BP) and pulse 
rate measurements.  Supine blood pressure (BP; systolic and diastolic) and pulse rate will be 
evaluated after at least 5 minutes rest.   
 
7.1.1.12 Serum Chemistry, Lipids, Hematology 
At the Screening Visit, Day 7 Visit, and Day 30 (EOS/ET) Visit, samples for routine serum 
chemistry, lipids, and hematology will be collected (see Appendix 3 for specific tests).  
Fasting for serum chemistry and lipids will begin at midnight until testing. 
 
The samples will be analyzed by a central laboratory (with the appropriate accreditations or 
certifications).  If clinically indicated, tests may be taken at additional times.  Any clinical 
laboratory findings considered to be clinically significant changes from screening will be 
recorded as an AE on the eCRF (unless the laboratory finding is a feature of a specific 
diagnosis, when only the diagnosis will be recorded).  Any clinically significant abnormal 
values that persist will be followed until they have been resolved or the Investigator, in 
consultation with the Medical Monitor or designee, assesses them to be chronic or stable. 
 
7.1.1.13 Urinalysis 
At the Screening Visit, Day 7 Visit, and Day 30 (EOS/ET) Visit, urine samples for urinalysis will 
be collected (see Appendix 3 for specific tests).   
 
The samples will be analyzed by a central laboratory (with the appropriate accreditations or 
certifications).  If clinically indicated, tests may be taken at additional times.  Any clinical 
laboratory findings considered to be clinically significant changes from screening will be 
recorded as an AE on the eCRF (unless the laboratory finding is a feature of a specific 
diagnosis, when only the diagnosis will be recorded).  Any clinically significant abnormal 
values that persist will be followed until they have been resolved or the Investigator, in 
consultation with the Medical Monitor or designee, assesses them to be chronic or stable. 
 
7.1.1.14 Immunogenicity Sample Collection 
 
 
 
7.1.1.15 Screens for HIV and Hepatitis B and C 
At the Screening Visit only, blood samples for testing HIV antibody, hepatitis B surface 
antigen, and hepatitis C antibody will be collected. 
 


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The samples will be analyzed by a central laboratory (with the appropriate accreditations or 
certifications).  Any positive findings at the Screening will exclude subject from participating 
in the study. 
 
7.1.1.16 Screens for Alcohol / Drugs of Abuse 
At the Screening Visit, Baseline (prior to dosing) Visit, Day 7 Visit, and Day 30 (EOS/ET) Visit, 
urine samples for screening drugs of abuse and saliva samples for screening alcohol will be 
collected and performed (see Appendix 3 for specific tests).   
 
The samples will be analyzed at the study site.  Any positive findings at the Screening or 
Baseline Visit will exclude subject from participating in the study. 
 
7.1.1.17 Pregnancy Test 
At the Screening Visit, blood samples for pregnancy test for women of child bearing 
potential will be collected.  The samples will be analyzed by a central laboratory (with the 
appropriate accreditations or certifications).   
 
At the Baseline (prior to dosing) Visit and Day 30 (EOS/ET) Visit, urine samples for pregnancy 
test for women of child bearing potential will be collected.  The samples will be analyzed at 
the study site.  Any positive findings at the Screening or Baseline Visit will exclude subject 
from participating in the study.  See Section 8.5.2 in the event of any positive findings during 
the study. 
 
7.1.1.18 Study Drug Administration 
At the Baseline Visit, upon conducting all specified pre-dose assessment and confirming 
subjects remain eligible for the study, study drug will be administered.  Six subjects in a 
cohort will be treated with either EB-001 or placebo in a ratio of 5:1 in a double-blind 
manner. 
 
7.1.1.19 Standardized Facial Photography 
At the Baseline (prior to dosing) Visit, and at all subsequent scheduled clinic visits till Day 30 
(EOS/ET) visit, standardized facial photographs will be taken per instructions in the study 
manual(s). 
 
The facial photograph assessments will be conducted by a central facility.  Results from the 
assessments will be used for reference purpose only and not be used to influence efficacy 
endpoint assessment at the site. 
 


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7.1.1.20 Facial Wrinkle Scale – Subject Assessment 
At the Screening Visit, Baseline (prior to dosing) Visit, and at all subsequent scheduled clinic 
visits till Day 30 (EOS/ET) visit, FWS at maximum frown and at rest will be assessed by the 
subject.  Subjects will be provided the Photonumeric Guide prior to self-assessment to assist 
and standardize grading of GL severity.  The FWS is a four-point scale that indicates severity 
of GL as follows: 0 = none, 1 = mild, 2 = moderate, or 3 = severe (see Appendix 2 for sample 
FWS assessment sheet). 
 
7.1.1.21 Facial Wrinkle Scale – Investigator Assessment 
At the Screening Visit, Baseline (prior to dosing) Visit, and at all subsequent scheduled clinic 
visits till Day 30 (EOS/ET) visit, FWS at maximum frown and at rest will be assessed by the 
Investigator.  Investigator will be provided the Photonumeric Guide prior to assessment to 
assist and standardize grading of GL severity.   The FWS is a four-point scale that indicates 
severity of GL as follows: 0 = none, 1 = mild, 2 = moderate, or 3 = severe (see Appendix 2 for 
sample FWS assessment sheet). 
 
7.2 Laboratory Procedures/Evaluations 
7.2.1 Clinical Laboratory Evaluations 
See Sections 7.1.1.12, 7.1.1.13, 7.1.1.14, 7.1.1.15, 7.1.1.16, and 7.1.1.17. 
 
7.2.2 Specimen Preparation, Handling, and Storage 
See Laboratory Manual for instructions of specimen preparation, handling, and storage.  
 
7.2.3 Specimen Shipment 
See Laboratory Manual for instruction of specimen shipment.  
 
7.2.4 Volume of Blood Collected 
The estimated total blood volume collected throughout the study for clinical laboratory and 
immunogenicity tests is summarized in Table 4 and is expected to be approximately 59.5 mL. 
 


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Table 4  
Total Blood Volume Collected for Each Subject 
Test 
Blood Sample Volume 
Number of Tests 
Total Volume 
Hematology1 
4 mL 
3 
12 mL 
Serum chemistry1, Lipids, Serum 
pregnancy test2 
8.5 mL 
3 
25.5 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 
 
 
59.5 mL 
1  Additional blood may be collected for safety laboratory tests, if clinically indicated 
2  Female of child bearing potential only 
 
7.3 Study Schedule 
7.3.1 Screening Visit (Days -30 to -1) 
Screening (Visit 1, Days -30 to -1, inclusive) will include the procedures and evaluations set 
forth in Section 7.3.7. 
 
7.3.2 Baseline Visit (Day 0) 
Baseline measurements and confirmation of subject eligibility will take place on Day 0. 
Procedures and evaluations prior to and after dose administration are set forth in Section 
7.3.7. 
 
7.3.3 Follow-Up Visits (Days 1, 2, 7, AND 14) 
Follow-up visits will take place on Days 1 (±2 hours), 2 (±4 hours), 7 (±12 hours), and 14 (±1 
day).  All procedures in each visit will be performed within the specified window.  Procedures 
and evaluations for each follow-up visit are set forth in Section 7.3.7. 
 
7.3.4 End of Study (Day 30) / Early Termination Visit 
Subject is considered to have completed the study after procedures and evaluations of Day 
30 (±2 days) are performed.  All procedures will be performed within the specified window.  
End of study (EOS) visit will include procedures and evaluations set forth in Section 7.3.7. 
 
In the event of early termination (ET), every attempt should be made to have subject return 
to the site to complete procedures and evaluations set forth in Section 7.3.7. 
 
7.3.5 Final Follow-Up Visit 
The final follow-up visit on Day 42 (±2 days) will include the procedures and evaluations set 
forth in Section 7.3.7.  All procedures will be performed within the specified window.   


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7.3.6 Unscheduled Visit 
Unscheduled Visit, at the discretion of the Investigator, may occur and appropriate 
procedures and evaluations will be conducted and documented in the eCRF.   


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7.3.7 Schedule of Events Table 


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7.4 Concomitant Medications and Treatments 
Throughout the study, the following concomitant medications and treatments are allowed 
and will be recorded. 
• Regular moisturizer or sunblock creams or lotions. 
• Medications used for controlled systemic disease or other medical conditions. 
• Vitamins and herbal medicines. 
• Acetaminophen for symptomatic relief of pain on an as needed basis, as prescribed 
by the Investigator.   
 
The Investigator must notify the Sponsor if participants take other concomitant medications 
during the study.  The decision to allow the subject to be enrolled into the study or take 
medications during the study will be made jointly by the Sponsor and Investigator, based on 
their opinion that the use of the medication is unlikely to compromise the safety of the 
subject or the interpretation of the study data. 
 
7.5 Prohibited Medications, Treatments, and Procedures 
During the study, subjects may not use the following medications, or have following 
treatments/procedures performed until after the EOS Visit. 
• Any topical retinoid therapy or topical hormone cream applied to the face unless 
they have been on a consistent dose regimen and maintained the same regimen for 
at least 6 months before enrollment. 
• Any oral retinoid drugs within 12 months of enrollment. 
• Any drugs used for skin conditions within 3 months of enrollment.  
• Any non-ablative resurfacing laser or light treatment, microdermabrasion, superficial 
peels within 3 months of enrollment. 
• Any facial cosmetic procedure with medium depth to deep facial chemical peels (e.g., 
trichloroacetic acid [TCA] and phenol), or mid facial or periorbital laser skin 
resurfacing within 3 months of enrollment. 
• Any mid-facial or periorbital treatment with non-permanent soft tissue fillers within 
12 months of enrollment. 
• Any history of botulinum neurotoxin treatment of any serotype. 
 
7.6 Subject Restriction 
The following restrictions apply: 
• Female of childbearing potential must agree to use dual methods of contraception 
from the day of dosing for 3 months.  Female subjects using oral contraception must 
have initiated treatment at least 2 months prior to the day of dosing.   


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• Male subjects with partner(s) of childbearing potential must agree to use dual 
methods of contraception from the day of dosing for 3 months, 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 42). 
• Subjects should not consume more than moderate amount of alcohol per day (i.e., 1 
drink per day for women or 2 drinks per day for men). 
 


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8 ASSESSMENT OF SAFETY 
8.1 Specification of Safety Parameters 
All of the following safety endpoints will be recorded on the eCRF. 
• Incidence and severity of TEAEs and SAEs. 
• Focused neurologic assessment for potential SOT. 
• Incidence of abnormal findings in laboratory tests, ECG, physical examination, and 
vital signs (pulse rate, respiratory rate, and blood pressure). 
• Urine pregnancy test for women of childbearing potential. 
 
8.1.1 Definition of Adverse Events (AE)  
Information about adverse events, 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 (FDA 1995), 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.  Examples 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. 


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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 
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 
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 of Medically Significant 


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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 eCRF. 
 
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 or possibly related to participation in the research (“possibly related” means 
there is a reasonable possibility that the incident, experience, or outcome may have 
been caused by the procedures involved in the research). 


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• Suggests that the research places participants or others at a greater risk of harm 
(including physical, psychological, economic, or social harm) than was previously 
known or recognized.  
 
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 CTCAE version 4.03 (CTCAE 2010).  AEs that do not 
have a corresponding CTCAE term will be assessed according to their impact on the 
participant’s ability to perform daily activities as listed below. 
• Mild (grade 1): The AE does not interfere in a significant manner with the subject’s 
normal functioning level—it may be an annoyance. 
• Moderate (grade 2): The AE produces some impairment of functioning, but is not 
hazardous to health—it is uncomfortable or an embarrassment. 
• Severe (grade 3): The AE produces significant impairment of functioning or 
incapacitation and is a definite hazard to the subject’s health. 
• Life threatening (grade 4): Life threatening or disabling. 
• Fatal (grade 5): Causes death of the participant. 
 
These five 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 eCRF.  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 considered related 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. 


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• 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 events). 
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 


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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.  
 
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, whether or not related 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. 
 


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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. 
 
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: 
 


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• 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) 
 
Bonti or designee will provide the Investigator with alternative contact information if the 
Medical Monitor will not be available. 
 
These events should continue to 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 ICF.  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 dual methods of 
contraception from the day of dosing until 3 months afterwards.  Female subjects using oral 
contraception must have initiated treatment at least 2 months prior to the day of dosing.  All 


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male subjects with partner(s) of childbearing potential must agree 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. 
 
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 pregnancy. 
 
The Investigator will be required to complete the Pregnancy Notification 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 Notification Follow-up 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 Data Review Team (DRT) 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 DRT 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.   
 


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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 GCP, and applicable regulatory 
requirements. 
 
A separate clinical monitoring plan (CMP) should 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.  
 


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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 
All statistical analyses for all safety and efficacy endpoints will be descriptive summary 
statistics.  Subjects who received placebo will be pooled across cohorts.  Safety data will be 
evaluated by assessing the various dose groups of EB-001 versus the placebo group.   
 
10.3 Analysis Datasets 
The safety set will include all randomized subjects who received at least 1 dose of study drug 
and have at least 1 safety assessment thereafter.   
 
The efficacy set will include all randomized subjects who received at least 1 dose of study 
drug and have at least 1 efficacy assessment thereafter.   
 
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 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. 
 
10.4.2 Analysis of the Primary Efficacy Endpoint(s) 
Baseline characteristics and change from baseline (CBL) of Investigator’s assessment of GL 
severity at maximum using the FWS will be summarized using descriptive statistics, with 
details provided in patient listings.  
 


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10.4.4 Safety Analyses 
10.4.4.1 Demographics and Baseline Characteristics  
Demographic and baseline characteristics (medical history, physical examination, prior 
medications) will be summarized using descriptive statistics, with details provided in patient 
listings. 
 
10.4.4.2 Prior and Concomitant Medications  
All prior and concomitant medications will be assigned a generic name and a drug class 
based on the World Health Organization (WHO) Dictionary.  Prior and concomitant 
medications will be listed and summarized by drug class. 
10.4.4.3 Completion of the Study and Withdrawals  
Withdrawals and the reason for withdrawal (AE(s), protocol non-compliance, lost to 
follow-up, failed to return, did not meet entrance criteria, voluntary withdrawal, and other 
reasons) will be tabulated.  The number and percentage of subjects who complete the study 
and who withdraw from the study will be tabulated. 
 
10.4.4.4 Tolerability Analysis  
Tolerability will be assessed at each dose level of EB-001/placebo by tabulating the number 
and percentage of subjects who develop one or more of the toxicity criteria in Table 3.  If 
2 or more EB-001-treated subjects within a cohort at a particular dose level of EB-001 
develop any of the intolerable toxicities specified in Table 3 and if these are considered to be 
related to EB-001, then that dose level will be considered an intolerable dose.  The previous 
tolerated dose tested will be considered the highest tolerated dose (see Section 4.1.1). 
 
10.4.4.5 Adverse Events  
Adverse events will be classified into standard terminology using the Medical Dictionary for 
Regulatory Activities (MedDRA).  Adverse events will be listed by event description 
(MedDRA-preferred term), 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.  Additionally, data may be grouped for analysis by different levels of the MedDRA 


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hierarchy.  The incidence of AEs, the incidence of treatment-related AEs, and the severity of 
AEs will be tabulated 
 
Serious adverse events, treatment-related SAEs (with subsets for SAEs resulting in death and 
non-fatal SAEs) and subjects who withdraw due to an AE will be tabulated. 
 
10.4.4.6 Clinical Laboratory Tests  
Clinical laboratory test parameters will be listed for individual subjects.  Baseline for clinical 
laboratory parameters will be defined as the last evaluation before dosing with study 
treatment.  For each parameter, with the exception of urinalysis parameters, summary 
statistics, including mean absolute change from baseline, will be calculated for each measure 
and summarized; urinalysis results will be listed but not summarized.  In addition, for 
leukocyte and lymphocyte counts, percentage change from baseline will be tabulated.   
 
Each clinical laboratory test will be defined to be “Low”, “Normal”, or “High”, according to 
the normal reference range from the clinical laboratory.  The number and percentage of 
subjects who have a shift from within to outside the normal reference range (and vice versa) 
from baseline to each follow-up visit will be summarized.  
 
Each clinical laboratory test will also be assigned to a grade based on the CTCAE v4.03 
(CTCAE 2010).  The number and percentage of subjects who have Grade 2, Grade 3, or 
Grade 4 laboratory value will be summarized. 
 
10.4.4.7 Vital Signs  
Vital signs results (including BP [systolic and diastolic], pulse rate, and body temperature) 
will be listed for individual subjects.  Baseline for vital signs measurements will be defined as 
the last evaluation before dosing with study medication.  Summary statistics, including mean 
change from baseline, will be determined for each measure and will be tabulated.   
 
Vital signs will be reviewed for notable abnormalities according to the criteria in Table 6, and 
clinically notable vital sign abnormalities will be listed.  The number and percentage of 
subjects who have a clinically notable vital sign abnormality will be summarized. 
 
Table 6  
Criteria for Clinically Notable Vital Sign Abnormalities 
Parameter 
High Threshold 
Low Threshold 
Systolic BP 
>30 mmHg increase from baseline 
>30 mmHg decrease from baseline 
Diastolic BP 
>20 mmHg increase from baseline 
>20 mmHg decrease from baseline 
Pulse rate 
>120 beats/min and an increase in pulse 
rate of ≥15 beats/min from baseline 
<40 beats/min and a decrease in pulse 
rate of ≥15 beats/min from baseline 
Body temperature 
>39.0°C (= >102.2°F) 
<35.0°C (= <95.0°F) 
 


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10.4.4.8 Electrocardiograms  
ECG intervals/durations (RR, PR, QT, QTcF, and QTcB intervals and QRS duration) and HR will 
be listed for individual subjects.  Baseline for ECG intervals/durations will be defined as the 
mean of the triplicate values recorded on the last evaluation before dosing with study 
medication.  Summary statistics, including mean change from baseline, will be determined 
for each measure and will be tabulated.   
 
Electrocardiographic intervals and durations will be reviewed for notable abnormalities 
according to the criteria in Table 7, and clinically notable abnormalities will be listed.  In 
addition, other ECG findings considered to be clinically significant (for example, rhythm 
disturbances, conduction abnormalities, T wave/ST segment abnormalities, etc.) will also be 
listed.  The number and percentage of subjects who have a clinically notable ECG interval 
abnormality or other clinically significant ECG finding will be summarized.   
 
Table 7  
Criteria for Clinically Notable ECG Interval Abnormalities 
Interval/Duration 
High Threshold 
Low Threshold 
PR interval 
PR interval ≥220 msec 
PR interval ≤120 msec 
QRS duration 
QRS duration ≥120 msec and an increase in QRS 
duration of ≥20 msec from baseline 
– 
QT interval 
QT interval >500 msec 
– 
QTc intervals1 
Males: 
QTc interval ≥450 msec and an increase in 
QTc interval of ≥60 msec from baseline 
or QTc interval >500 msec 
– 
Females: QTc interval ≥470 msec and an increase in 
QTc interval of ≥60 msec from baseline 
or QTc interval >500 msec 
 1 Fridericia’s and Bazett’s corrections (QTcF and QTcB, respectively) 
 
10.4.4.9 Physical and Focused Neurological Examinations 
Findings of physical and focused neurological examinations will be listed for individual 
subjects and summarized. 
 
For the evaluation of SOT terms, the criteria for Grading are: 
 
• Grade 1 (Mild): Asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated.  
• Grade 2 (Moderate): Minimal, local or noninvasive intervention indicated; limiting 
age-appropriate instrumental Activities of Daily Living (ADL).  Instrumental ADL refer 
to preparing meals, shopping for groceries or clothes, using the telephone, managing 
money, etc. 
• Grade 3 (Severe or medically significant but not immediately life-threatening): 
Hospitalization or prolongation of hospitalization indicated; disabling; limiting self-


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care ADL.  Self-care ADL refer to bathing, dressing and undressing, feeding self, using 
the toilet, taking medications, and not bedridden 
• Grade 4 (Life-threatening consequences): Urgent intervention indicated.  
• Grade 5 (Death related to AE). 
 
10.4.4.11 Urine Drug Test 
Results of urine drug test will be listed for individual subjects.  Each test will be defined to be 
“negative” or “positive”, according to the normal reference range from the clinical 
laboratory.  The number and percentage of subjects who are “positive” or “negative” in each 
visit will be summarized. 
 
10.4.4.12 Pregnancy Test 
Results of pregnancy test will be listed for individual subjects.  Each test will be defined to be 
“negative” or “positive”, according to the normal reference range from the clinical 
laboratory.  The number and percentage of subjects who are “positive” or “negative” in each 
visit will be summarized. 
 
10.4.5 Planned Interim Analyses 
No formal interim analysis is planned. 
 
10.4.6 Exploratory Analyses 
Exploratory analyses of efficacy as appropriate may be conducted. 
 
10.5 Sample Size 
This is the first human study to evaluate the safety and efficacy of EB-001, and therefore 
there are no data on which to base sample sizes.  However, a sample size of 5 subjects per 


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cohort (n = 5 EB-001, n = 1 placebo) is considered to provide sufficient initial information on 
the estimation of the safety and tolerability of EB-001.   
 
With 5 subjects receiving each dose level of EB-001 per cohort, an AE that occurs with a true 
frequency of 50% will be detectable with 96.9% probability within a given cohort.  Combined 
across cohorts, with 35 subjects receiving EB-001, an AE that occurs with a true frequency of 
10% will be detectable with greater than 97.5% probability.  The probability of detecting AEs 
is shown in Table 8: 
 
Table 8  
Probability of Detecting Adverse Events that Occur at Various Frequencies 
True Event 
Rate 
Probability of Observing at Least 
1 Event with 5 Completed Subjects 
Probability of Observing at Least 
1 Event with 35 Subjects 
0.01 
4.9% 
29.7% 
0.1 
41.0% 
97.5% 
0.2 
67.2% 
>99% 
0.5 
96.9% 
>99% 
 
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. Patients 
are considered to be randomly assigned to the study when they are assigned to receive 
either EB-001 or placebo.  Within each cohort, subjects will be randomly allocated to receive 
either EB-001 or placebo in a 5:1 ratio.  The dosage level of EB-001 will not be randomized. 
 
The study will be conducted in a double-blinded manner.  Study drugs between EB-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 will be aware of the EB-001 dose level in 
each dose cohort; however, except for a limited number of Sponsor staff (see below), they 
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 


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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 by an Interactive Voice Response System 
(IVRS) or Interactive Web Response System (IWRS) system.   
 
In the rare 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 
IVRS or IWRS 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 of Sponsor Personnel 
During this study, staff of Bonti and designee will be blinded to treatment allocation, except 
as described in this section.  The periodic DRT 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). 
 
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.  Any 
personnel from Bonti and designee who become unblinded to study safety and efficacy data 
will be documented and no longer participate in day-to-day management of the study. 
 
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 


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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.  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 24-hour IVRS/IWRS.  Details of the process 
to be followed and the telephone number are provided in the study manual(s) provided to 
the site.  In the event that the IVRS/IWRS is used to perform a code break, Bonti or designee 
will be notified immediately by the IVRS/IWRS using an automated notification.   
 
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. 
 


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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.  
 
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.  
 


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12 QUALITY ASSURANCE AND QUALITY CONTROL 
See Section 9. 
 


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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. 
 
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.  


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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.   
 
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 in case there are substances discovered about which 
we are not currently aware that might help us better understand or develop treatments 
for glabellar line, 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 


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the trial’s completion or early termination and send a copy of the notification to the 
Sponsor. 
 


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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 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 
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 
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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.