Clinical trial NCT03193593
Conditions: Musculoskeletal Pain
Sponsor: Bonti, Inc.
Start date: 2017-08-29; Completion date: 2018-08-07
Enrollment: 66 participants; Allocation: RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
To determine the safety and efficacy of single intra-operative treatment of EB-001 IM injections into the Pectoralis Major (PM) in subjects undergoing breast augmentation with subpectoral implants

Detailed description:
This study will evaluate the safety and efficacy of EB-001 in decreasing post-surgical pain in patients undergoing surgical breast augmentation with subpectoral placement of the implants. Intramuscular (IM) injection of EB-001 into the PM bilaterally during surgery may decrease pain related to stretching of the PM by the implants.

The safety objective is to determine the safety and tolerability of single intraoperative treatment of EB-001 IM injections into the PM in subjects undergoing breast augmentation with subpectoral implants.

The efficacy objective is to evaluate the efficacy of intraoperative administration of EB-001 IM into the PM in reducing the pain and use of rescue pain medications in subjects undergoing breast augmentation with subpectoral implants.

Arms: arm 1: Intervention: Drug: Placebo

Single Saline Injection into the Pectoralis Muscle arm 2: Intervention: Drug: EB-001

1st Dose in escalation paradigm. Single Injection of active drug into the pectoralis muscle arm 3: Intervention: Drug: EB-001

2nd Dose in escalation paradigm, 1.6X Dose 1. Single Injection of active drug into the pectoralis muscle arm 4: Intervention: Drug: EB-001

3rd Dose in escalation paradigm, 3.3X Dose 1. Single Injection of active drug into the pectoralis muscle arm 5: Intervention: Drug: EB-001

4th Dose in escalation paradigm, 6.7X Dose 1. Single Injection of active drug into the pectoralis muscle arm 6: Intervention: Drug: EB-001

5th Dose in escalation paradigm, 10X Dose 1. Single Injection of active drug into the pectoralis muscle arm 7: Intervention: Drug: EB-001

6th Dose in escalation paradigm, 13.3X Dose 1. Single Injection of active drug into the pectoralis muscle
Interventions: intervention 1: Placebo intervention 2: EB-001
Intervention descriptions: intervention 1: Placebo- Single injection of saline into Pectoralis Muscle intervention 2: Single injection of EB-001 into Pectoralis Muscle

Protocol documents:
Prot_SAP_000.pdf: 
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CLINICAL STUDY PROTOCOL 
A Phase 2 Placebo-Controlled, Double Blind, Ascending Dose Cohort 
Study to Evaluate Safety and Efficacy of EB-001 Intramuscular (IM) 
Injections in Reducing Musculoskeletal Pain in Subjects Undergoing 
Elective Augmentation Mammoplasty (Breast Augmentation) 
 
Study Number: EB001-MA201 
 
 
IND Sponsor: Bonti, Inc. 
 
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 
 
Reviewed 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 on 
clinical trials, Good Clinical Practice (GCP), and protection of human subjects 
 
 
 
 
 
 _______________________  
 _______________________  
 ____________________  
 Investigator Printed Name 
Signature  
Date 
 
 
 


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TABLE OF CONTENTS 
TABLE OF CONTENTS .................................................................................................................. 4 
LIST OF TABLES ........................................................................................................................... 4 
LIST OF FIGURES ......................................................................................................................... 4 
 
LIST OF ABBREVIATIONS AND GLOSSARY OF TERMS ................................................................. 5 
 
LIST OF TABLES 
Table 1  
Probability of Detecting Adverse Events that Occur at Various Frequencies .. 19 
Table 2  
Schedule of Study Procedures, By Day ............................................................ 21 
Table 3  
Schedule of Pain Assessments (NPRS and NPRS-A), Use of Incentive 
Spirometry, and Pulmonary Function Test (SVC) After Surgery, During In-
Patient Stay ...................................................................................................... 24 
 
LIST OF FIGURES 
Figure 1  
Dose Escalation ................................................................................................ 19 
  
 
 
 


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LIST OF ABBREVIATIONS AND GLOSSARY OF TERMS 
Term 
Definition 
AE 
adverse event 
ALT (SGPT) 
alanine aminotransferase (= serum glutamic pyruvic transaminase) 
ANOVA 
Analysis of Variance 
ATC 
Anatomical Therapeutic Chemical 
AST (SGOT) 
aspartate aminotransferase (= serum glutamic oxaloacetic 
transaminase) 
AUC 
Area under the curve 
BMI 
Body Mass Index 
BoNT 
botulinum neurotoxin 
BoNT/A 
botulinum neurotoxin serotype A 
BoNT/E 
botulinum neurotoxin serotype E 
BP 
blood pressure 
BUN 
blood urea nitrogen 
CBL 
change from baseline 
CFR 
Code of Federal Regulations 
CMP 
clinical monitoring plan 
CRF 
case report form 
CRO 
Contract Research Organization 
DAS 
digital abduction score 
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 
EU 
European Union 
F-U 
follow up 
FDA 
Food and Drug Administration 
FEV1 
forced expiratory volume 1 
FIH 
first-in-human 
FVC 
forced vital capacity 


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Term 
Definition 
GCP 
Good Clinical Practice 
GGT 
gamma-glutamyl transferase 
GLP 
Good Laboratory Practices 
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 
IUD 
intrauterine device 
IVRS 
interactive voice 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 
mITT 
modified Intent to Treat 
mL 
Milliliter 
mouse LD50 
lethal dose to 50% of mice after intraperitoneal injection 
MRC 
Medical Research Council 


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Term 
Definition 
MRSD 
maximum recommended starting dose 
Msec 
Milliseconds 
NA 
not applicable 
Ng 
nano gram  
NPRS 
numerical pain rating scale 
NPRS-A 
NPRS administered after an activity 
NOAEL 
no observable adverse effects limit 
OHRP 
Office for Human Research Protections 
PACU 
post-anesthesia care unit  
PAD 
pharmacologically active dose 
PCV 
packed cell volume 
PI 
principal investigator 
PFT 
pulmonary function test 
PGA 
patient global assessment  
PM 
pectoralis major 
PP 
Per Protocol 
PR interval 
time between the onset of atrial depolarization and the onset of 
ventricular depolarization 
PRN 
as-needed 
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 


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Term 
Definition 
SD 
Standard Deviation 
SNAP 
synaptosomal-associated protein 
SOT 
spread of toxin 
SRC 
Safety Review Committee 
SUSAR 
suspected unexpected serious adverse reactions 
SVC 
slow vital capacity 
RR interval 
time elapsing between two consecutive R waves in the 
electrocardiogram. It is used to assess the ventricular rate. 
TCA 
trichloroacetic acid 
TEAE 
treatment emergent adverse event 
µg 
Microgram 
UP 
unanticipated problem 
US 
United States 
WBC 
white blood cell (Leukocyte) 
WHO 
World Health Organization 
 


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PROTOCOL SUMMARY 
Study Number: 
EB001-MA201 
Study Title: 
A Phase 2 Placebo-Controlled, Double Blind, Ascending Dose Cohort Study to Evaluate Safety 
and Efficacy of EB-001 Intramuscular (IM) Injections in Reducing Musculoskeletal Pain in 
Subjects Undergoing Elective Augmentation Mammoplasty (Breast Augmentation) 
Investigational Drug Product: 
EB-001 (Botulinum Neurotoxin Serotype E, BoNT/E) for injection. 
Study Objectives: 
Safety Objective: To determine the safety and tolerability of a single intraoperative treatment 
of EB-001 IM injections into the Pectoralis Major (PM) bilaterally in subjects undergoing 
breast augmentation with subpectoral implants. 
Efficacy Objective: To evaluate the efficacy of intraoperative administration of EB-001 IM into 
the PM in bilaterally in reducing the pain and use of rescue pain medications in subjects 
undergoing breast augmentation with subpectoral implants. 
 
Phase of Trial: 
Phase 2 
Clinical Hypothesis: 
Safety: A single treatment of EB-001 IM injected into the PM bilaterally has an acceptable 
safety and tolerability profile at the tested doses in subjects undergoing breast augmentation 
with subpectoral implant placements. 
Efficacy: A single treatment of EB-001 IM injected into the PM bilaterally reduces post-surgical 
musculoskeletal pain in subjects undergoing breast augmentation with subpectoral implants, 
at one or more of the doses tested in the study. 
Study Population: 
Healthy females 23 to 55 years of age, inclusive, undergoing primary, bilateral, cosmetic 
breast augmentation with subpectoral implants under general anesthesia (endotracheal or 
otherwise). 
Outcome Measures: 
Safety Measures:  
• Incidence and severity of treatment emergent adverse events (TEAEs) and serious 
adverse events (SAEs) 
• Assessment of AEs of special interest (post-operative dyspnea, tachypnea, tachycardia, 
pneumonia, atelectasis, and fever) 
• Focused neurologic examination for potential spread of toxin (SOT) 


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• Incidence of abnormal findings in laboratory tests, electrocardiogram (ECG), physical 
exam, and vital signs (pulse rate, respiratory rate, pulse oximetry and blood pressure) 
• 
 
• Serum/urine pregnancy test for women of childbearing potential 
Efficacy Measures: 
Primary Efficacy Measures: 
• Area under the curve (AUC) of subject’s assessment of pain using the Numeric Pain 
Rating Scale (NPRS) between 16 and 96 hour post-surgery (AUC16-96). 
 
 
 
 
  
 
  
 
  
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
Study Design: 
This will be a randomized, placebo-controlled, double blind, single ascending dose cohort 
study. The study will be conducted at up to two surgical centers that specialize in breast 
augmentation surgeries. The study will enroll up to 66 subjects (Figure 1).
 
 
 
 
 
  
 
 
 
 


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The study will include a visit for screening and pre-surgical assessments. On the day of surgery 
(Day 1), eligible subjects will be admitted to an inpatient clinic and a single treatment of EB-
001 IM will be given intraoperatively via IM injections into each PM. The subject will remain 
in-clinic and be assessed for 96 hours post-surgery. Follow up visits will be scheduled at Days 
8, 15, and 29 (Table 2 and Table 3). 
Investigational (Study) Sites: 
It is expected that up to 2 clinical surgical sites will conduct the study and enroll up to 66 
subjects, or up to 86 subjects if up to 5 additional cohorts are enrolled. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Duration: 
The expected study duration for each subject includes up to 4 weeks in screening, and 
approximately 4 weeks from the day of surgery to the last visit, for a total duration of 8 weeks 
from the signing the Informed Consent Form (ICF) to the last study visit. 
Inclusion Criteria: 
An individual must meet ALL the following criteria to participate in this study: 
1. Women 23 to 55 years of age, inclusive 
2. Women who are in good health as determined by medical history, physical 
examination, clinical laboratory studies, ECGs, vital signs, and Investigator judgment 


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3. Scheduled to undergo primary breast augmentation under general anesthesia 
(endotracheal or otherwise) with: 
a. 
Sub-pectoral implants placement, 
 
 
 
 
4. American Society of Anesthesiologist (ASA) Physical Class 1-2 
5. Women of non-childbearing potential or postmenopausal (at least 12 consecutive 
months of amenorrhea) 
6. Women of childbearing potential must not be pregnant, lactating, or planning to 
become pregnant during the study 
7. Women of childbearing potential agreeing to use either: 
a. 
a highly effective method of contraception with failures rates less than 1% per 
year such as implant, intrauterine device (IUD), or confirmed sterilization and 
sterilization procedure at least 3 months prior to the day of dosing 
b. 
dual methods of contraception with overall failures rate less than 1% per year 
such as injectable, pill, patch, ring, and diaphragm from the day of dosing for 
3 months (subjects using oral contraception must have initiated treatment at 
least 2 months prior to the day of dosing) 
8. Willing and able to complete protocol requirements and instructions, which includes 
completion of all required visits, procedures and in-clinic stays until the end of the 
study 
9. Willing and able to sign and date IRB-approved informed consent 
10. Able to speak, read, and understand the language of the informed consent form (ICF) 
and study questionnaires 
Exclusion Criteria: 
An individual who meets ANY of the following criteria will be excluded from participation in 
this study: 
1. History of surgical procedure involving the breast, including, but not limited to, breast 
augmentation. History of minor localized breast biopsy is not exclusionary if it 
occurred at least 1 year prior to the screening visit, and if considered not clinically 
significant in the opinion of the investigator. 
2. Pre-existing lung disease that could impact subject safety in the opinion of the 
investigator 
3. History of smoking within the past two years 
 
7. Documented diagnosis of chronic pain condition, or other painful pre-operative 
condition that, in the opinion of the investigator, may require analgesic treatment in 
the post-operative period (e.g. significant joint pain, neuropathic pain) 


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8. Known hypersensitivity to any botulinum toxin serotype or to any component of the 
formulation 
9. Reported use of any botulinum toxin within 3 months prior to the date of surgery 
10. Anticipated use of any botulinum toxin of any serotype during the study 
11. Use of long acting opioids within 3 days or any opioid medication within 24 hours prior 
to surgery 
 
 
 
 
 
 
16. History of alcohol or drug abuse in the last 3 years, based on investigator judgement 
17. 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  
18. Subject plans to donate blood or plasma from 30 days prior to screening until last 
follow-up visit (Day 29) 
19. Reported pain score of 2 or more at screening on the 11-point scale NPRS-A following 
strength testing with PM activation 
Study Drug: 
 
 
 
Placebo: 
Preservative-free, sterile saline solution (0.9% Sodium Chloride Injection, USP). 
Dosage: 
The total dose of active drug
 
 
The injection paradigm will be 
provided in the injection technique and surgical manual. 
Study drug injections will be performed 
 
 
 
 
 
 
 


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Stopping Criteria for Dose Escalation: 
Upon completion of Day 5 assessments for the last subject dosed in the prior sentinel group 
 
 
 
 
 
 
  
 
 
  
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
The Medical Monitor or designee may request unblinding of treatment assignment with any 
of the criteria set forth above, and may discuss the treatment identity with the Investigator, 
before any further subjects are dosed.  


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Flexibility in Dose Adjustment: 
If an intolerable dose is identified (based on one of the above 5 criteria), a lower dose may be 
evaluated as proposed by the SRC (Figure 1). This lower dose may be a repeat of the prior 
lower dose cohort or an intermediary dose between the intolerable dose and prior lower dose 
cohort. If the dose is an intermediary dose, a sentinel group consisting of 2 subjects (1 active: 
1 placebo) will be dosed first. The SRC will review all available safety data of the prior sentinel 
group through at least Day 5 post-operatively, and 4 additional subjects (3 active: 1 placebo) 
will be dosed upon approval. 
 
  
 
 
  
 
 
 
 
  
Screening: 
Written informed consent form (ICF), demographics and baseline characteristics, 
inclusion/exclusion criteria, medical/surgical history, height, weight and BMI, complete 
physical and focused neurological examinations, prior and concomitant medications, 12-lead 
ECG, vital signs, clinical laboratory tests (serum chemistry, lipids, hematology, urinalysis), 
immunogenicity sample collection, screens for Human Immunodeficiency Virus (HIV) and 
Hepatitis B and C, screens for alcohol and drugs of abuse, serum pregnancy test, strength 
testing and pain assessment (NPRS-A) with PM activation, and pulmonary function test (PFT; 
SVC, FVC and FEV1). 
Safety Assessments: 
Safety assessments will include collection and evaluation of TEAEs, physical and focused 
neurologic examinations (for potential SOT events), prior and concomitant medications, 
triplicate ECG, vital signs, clinical laboratory tests (serum chemistry, lipids, hematology, and 
urinalysis), medical/surgical history, serum/urine pregnancy 
 
 Safety assessments will also include collection and evaluation of TEAEs of 
Special Interest including post-operative dyspnea, tachypnea, tachycardia, pneumonia, 
atelectasis, and fever, which will be closely monitored. 
Efficacy Assessments 
• Overall pain scores at rest using the NPRS  
o NPRS is self-assessed by the study subject for their current pain according to an 
11- point numeric pain rating scale (NPRS; 0 - 10) where 0 equates to no pain, and 


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10 equates to the worst pain imaginable.  
o 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
• PGA of pain control  
o Each subject will be asked the following question: Overall, please rate how well 
your pain has been controlled during the last 24 hours? Poor (0), Fair (1), Good (2), 


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or Excellent (3). 
• Use of rescue medications over the post-surgical assessment periods 
• 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
General Statistical Considerations: 
The final analysis will be performed when all subjects have completed Day 29 or exited early 
from the study.  
Study Populations 
The modified Intent to Treat (mITT) population will include all randomized patients who 
receive study drug. All efficacy analyses will be performed using this population. Analyses will 
be performed on subjects using their randomized treatment group. 
The Per Protocol (PP) population will include all subjects in the mITT population with no major 
protocol violations. The primary efficacy variable will also be analyzed using this population. 
The Safety population will include all subjects exposed to any amount of study drug. All safety 
analyses will be performed using the safety population.  
Sample Size 
Subjects in each cohort will be randomly allocated to receive either EB-001 or placebo. 
 
 
 
 
 
All placebo subjects will be pooled for statistical analyses. All statistical analysis will be 
detailed in the statistical analysis plan (SAP), which will undergo formal sign off prior to 
database lock.  


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With at least 4 subjects receiving each dose level of EB-001 per cohort, an AE that occurs with 
a true frequency of 50% will be detectable with a 93.8% probability within a given cohort. 
Combined across all 6 cohorts, with up to 48 subjects receiving EB-001, an AE that occurs with 
a true frequency of 10% will be detectable with a 99.4% probability. The probability of 
detecting AEs is shown below (Table 1): 
Table 1  
Probability of Detecting Adverse Events that Occur at Various Frequencies 
True Event 
Rate 
Probability of Observing at Least 
1 Event with 4 Completed Subjects 
Probability of Observing at Least 
1 Event with 48 Subjects 
0.01 
3.9% 
38.3% 
0.1 
34.4% 
99.4% 
0.2 
59.0% 
>99% 
0.5 
93.8% 
100% 
Analyses 
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, ECG 
measures, and pulmonary functions), including mean absolute change from baseline, will be 
summarized by treatment group. 
Efficacy parameters including, but not limited to, AUC of overall pain assessment at rest, pain 


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assessment with passive and active arm abduction, amount of allowed rescue medications, 
and PGA of pain control will be summarized by treatment group. Statistical hypothesis testing 
will be performed, and one-sided p-values will be provided. The primary efficacy objective is 
to estimate the reduction of pain, assessed as an AUC for the NPRS pain scores over the 16-
96 hour post-surgical period. 
While this is not a formally powered study for efficacy analyses, efficacy data from the study 
will allow assessment of efficacy signal or trends, and exploration of the efficacious dose 
range. This will allow dose selection for future studies. 
If a subject requests rescue medication, the pre-rescue pain NPRS and NPRS-A assessments 
will be carried forward for 4 hours. Handling of missing data for subjects who discontinue the 
study will be specified in the SAP. 
 


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Table 2  
Schedule of Study Procedures, By Day 


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