A Phase 3b, Randomized, Double-Blind, Placebo-Controlled Study to Assess Aesthetic Improvement and Onset of QM1114-DP Treatment Effect in Subjects With Moderate to Severe Glabellar Lines
Phase: PHASE3
Conditions: Glabellar Frown Lines
Sponsor: Galderma R&D

CONFIDENTIAL 
Page 1 of 86
CLINICAL STUDY PROTOCOL
PROTOCOL NUMBER: 43QM2106
CONFIDENTIAL
This document contains confidential, proprietary information
All the information provided to the investigator and his/her staff and all data obtained through 
this Q-Med AB clinical study protocol are confidential.  Q-Med AB is the owner of all 
information included in this protocol as sponsor and then sponsor reserves all proprietary 
rights. No information may be disclosed to any third party without prior written consent from 
Q-Med AB.
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Table of Contents
TITLE PAGE........................................................................................................................................ 2
CLINICAL STUDY SCHEMATIC AND FLOW CHART............................................................ 16
SCHEDULE OF ASSESSMENTS.................................................................................................... 18
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ................................................. 20
1.
BACKGROUND AND RATIONALE .............................................................................. 24
1.1
Medical Background and Short Rationale for the Clinical Study.................................. 24
1.2
Study Product Profile ......................................................................................................... 25
1.2.1
Drug Profile.................................................................................................................... 25
1.2.2
Pre-Clinical Documentation.......................................................................................... 25
1.2.3
Clinical Documentation................................................................................................. 26
1.2.4
Dose Rationale................................................................................................................ 27
1.3
Risk/Benefit Assessment..................................................................................................... 27
2.
CLINICAL STUDY OBJECTIVES, ENDPOINTS, AND CLINICAL 
HYPOTHESIS..................................................................................................................... 28
2.1
Clinical Study Objectives ................................................................................................... 28
2.1.1
Primary Efficacy Objective and Endpoint .................................................................. 28
2.1.2
Secondary Efficacy Objectives and Endpoints............................................................ 29
2.1.4
Safety Objectives and Endpoints.................................................................................. 31
2.2
Clinical Hypothesis ............................................................................................................. 31
3.
OVERALL CLINICAL STUDY DESCRIPTION........................................................... 31
4.
CLINICAL STUDY DURATION AND TERMINATION ............................................. 31
5.
SELECTION AND DISPOSITION OF CLINICAL STUDY POPULATION............. 32
5.1
Number of Subjects............................................................................................................. 32
5.2
Clinical Study Population Characteristics........................................................................ 32
5.2.1
Inclusion Criteria........................................................................................................... 32
5.2.2
Exclusion Criteria.......................................................................................................... 33
5.3
Medical History................................................................................................................... 34
5.4
Previous and Concomitant Therapies............................................................................... 35
5.4.1
Definition ........................................................................................................................ 35
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5.4.2
Categories ....................................................................................................................... 35
5.4.3
Recording........................................................................................................................ 35
5.4.4
Authorized Concomitant Therapies............................................................................. 35
5.4.5
Prohibited Concomitant Therapies.............................................................................. 35
5.5
Procedures/Reasons for Subject Discontinuation ............................................................ 36
6.
CLINICAL SUPPLIES ...................................................................................................... 37
6.1
Clinical Supply Identification and Use.............................................................................. 37
6.1.1
QM1114-DP.................................................................................................................... 37
6.1.2
Placebo............................................................................................................................ 37
6.1.3
Study Products(s) Description ...................................................................................... 38
6.1.4
Subject Identification Number ..................................................................................... 38
6.1.5
Method of Treatment Assignment................................................................................ 38
6.1.6
Kit Number/Randomization Number .......................................................................... 38
6.1.7
Instructions for Use and Administration..................................................................... 39
6.1.7.1
Treatment Procedure ............................................................................................... 39
6.1.7.2
Post-treatment Care ................................................................................................. 40
6.1.7.3
Treatment Regimen.................................................................................................. 40
6.3
Supplies Management......................................................................................................... 41
6.3.1
Accountability ................................................................................................................ 41
6.3.2
Storage of Study Product(s).......................................................................................... 41
6.3.3
Dispensing and Return .................................................................................................. 41
6.3.4
Treatment Compliance Management and Record...................................................... 41
6.3.5
Dose Modification .......................................................................................................... 41
6.3.6
Product Quality Complaints......................................................................................... 41
6.4
Blinding................................................................................................................................ 42
6.4.1
Verification of Blinding................................................................................................. 42
6.4.2
Unblinding During the Clinical Study ......................................................................... 42
7.
CLINICAL STUDY ASSESSMENTS .............................................................................. 43
7.1
Efficacy Assessments........................................................................................................... 43
7.1.1
Global Aesthetic Improvement Scale........................................................................... 43
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8.
CLINICAL STUDY VISITS DESCRIPTIONS AND PROCEDURES......................... 52
8.1
Description of Clinical Study Visits................................................................................... 52
8.1.1
Screening/Visit 1 (-14 days to Day 0)............................................................................ 52
8.1.2
Baseline/Visit 2 (Day 0).................................................................................................. 53
8.1.3
Days 1, 2, 3/Visits 3, 4, 5 ................................................................................................ 55
8.1.4
Day 4/Visit 6 ................................................................................................................... 56
8.1.5
Month 1/Visit 7 (± 5 days) ............................................................................................. 57
8.1.6
Month 3/Visit 8 (± 5 days) ............................................................................................. 58
8.1.7
Month 6/Visit 9 (± 5 days) ............................................................................................. 58
8.1.8
Months 7-11/Visits 10-14 (± 5 days).............................................................................. 59
8.1.9
Month 12 or Early Termination/Visit 15 (± 5 days).................................................... 60
8.2
Unscheduled Visits.............................................................................................................. 61
8.3
Subject Instructions............................................................................................................ 61
9.
STATISTICAL METHODS PLANNED.......................................................................... 62
9.1
Statistical and Analytical Plans ......................................................................................... 62
9.1.1
Data Transformations ................................................................................................... 62
9.1.2
Populations Analyzed and Evaluability....................................................................... 62
9.1.2.1
Intent-to-treat (ITT) Efficacy Population............................................................... 62
9.1.2.2
Per-protocol (PP) Efficacy Population.................................................................... 62
9.1.2.3
Safety Population...................................................................................................... 62
9.1.2.4
Imputation of Missing Data ..................................................................................... 62
9.1.3
Data Presentation and Graphics................................................................................... 62
9.1.3.1
Safety Analysis .......................................................................................................... 63
9.1.4
Withdrawals and Deviations......................................................................................... 63
9.1.5
Inferential Statistical Analyses ..................................................................................... 64
9.2
Sample Size Determination ................................................................................................ 64
9.2.1
Historical Data ............................................................................................................... 64
9.2.2
Assumptions ................................................................................................................... 64
9.2.3
Sample Size Calculation ................................................................................................ 64
9.2.4
Interim Analysis............................................................................................................. 64
10.
TRAINING / MONITORING / DATA MANAGEMENT / QUALITY 
ASSURANCE ...................................................................................................................... 65
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10.1
Personnel Training.............................................................................................................. 65
10.2
Clinical Monitoring............................................................................................................. 65
10.3
Data Management............................................................................................................... 65
10.4
Quality Assurance/Audit/Inspection ................................................................................. 66
10.5
Changes in Clinical Study Conduct/Amendments........................................................... 66
10.5.1
Clinical Study Conduct.................................................................................................. 66
10.5.2
Amendments................................................................................................................... 66
11.
ETHICS AND GENERAL CLINICAL STUDY CONDUCT 
CONSIDERATIONS .......................................................................................................... 66
11.1
Institutional Review Board ................................................................................................ 66
11.2
Ethical Conduct of the Clinical Study............................................................................... 66
11.3
Subject Information and Consent ..................................................................................... 67
11.4
Protection of Personal Data ............................................................................................... 67
11.5
Contractual Requirements................................................................................................. 68
11.6
Data Collection and Archiving........................................................................................... 68
11.6.1
Data Collection............................................................................................................... 68
11.6.2
Source Documentation................................................................................................... 68
11.6.3
Archives .......................................................................................................................... 68
11.7
Insurance ............................................................................................................................. 68
11.8
Publication Policy................................................................................................................ 69
11.9
Investigator and Administrative Structure ...................................................................... 70
12.
LITERATURE REFERENCE LIST...................................................................................... 71
13.
SUMMARY OF CHANGES ................................................................................................... 72
14.
APPENDICES .......................................................................................................................... 73
Appendix 7
Focused Physical Examination Form Example...................................................... 83
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Appendix 8
Adverse Events Potentially Suggestive of Remote Spread of Toxin..................... 85
SIGNED AGREEMENT OF THE CLINICAL STUDY PROTOCOL (CSP) ............................. 86
List of Tables
Table 1
Clinical Study Schematic................................................................................................. 16
Table 2
Schedule of Assessments................................................................................................. 18
Table 3
Description and Usage of the Study Products(s) ............................................................. 38
List of Figures
Figure 1 
Study Flow Chart............................................................................................................. 17
Figure 2
Injection Sites for Treating Glabellar Lines..................................................................... 40
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SYNOPSIS

Bilateral tubal ligation;

Combined (estrogen and progesterone containing) oral, 
intravaginal or transdermal contraceptives that inhibit 
ovulation as the primary mode of action, on a stable dose for 
at least 28 days prior to screening visit;

Intrauterine device (IUD) inserted at least 28 days prior to 
screening visit;

Intrauterine hormone-releasing system;

Partner vasectomized for at least three months prior to 
screening visit;

Progestogen-only 
oral, 
injectable 
or 
implantable 
contraceptives that inhibit ovulation as the primary mode of 
action, on a stable dose for at least 28 days prior to 
screening visit; or

Strict 
abstinence 
(i.e., 
refraining 
from 
heterosexual 
intercourse for the duration of the subject’s participation in 
the study).
7.
Time and ability to complete the study and comply with instructions.
8.
Understands the study requirements and signed the informed consent 
form (ICF).
Key Exclusion Criteria:
1.
Previous use of any botulinum toxin in facial areas within 9 months prior 
to study treatment.
2.
Anticipated need for treatment with botulinum toxin of any serotype for 
any reason during the study (other than the investigational product).
3.
Female who is pregnant, breast feeding, or intends to conceive a child 
during the study.
4.
Known allergy or hypersensitivity to any component of the 
investigational product (QM1114-DP) or any botulinum toxin serotype.
5.
Inability to substantially lessen GL by physically spreading them apart, 
as determined by the investigator. 
6.
Clinically significant abnormal focused physical exam finding(s) at 
screening or baseline visits, in the investigator’s opinion.
7.
Excessive skin laxity in the treatment area or periorbital area.
8.
Previous use of any hyaluronic acid soft tissue augmentation therapy in 
the glabella area within 6 months before baseline.
9.
Previous soft tissue
augmentation with any permanent (non-
biodegradable such as silicone, polyacrylamide, etc.) or semi-
permanent (i.e., calcium hydroxylapatite, poly-L-Lactic acid or 
polymethyl-methacrylate) product; lifting threads, or autologous fat in the 
treatment area.
10. History, presence, or predisposition of eyelid or eyebrow ptosis (heavy 
eyebrows), amblyopia (i.e., lazy eye), or previous surgery around the 
eye that may lead to the above events, as determined by the 
investigator.
11. Marked facial asymmetry, excessive dermatochalasis (i.e., excess of 
skin in eyelids), or marked periocular or eyebrow asymmetry.
12. Presence of scar(s), piercing(s), or tattoo(s) (including microblading of 
eyebrow or eyeliner) in the treatment area or around the treatment area 
that, in the investigator’s opinion, may interfere with study evaluations.
13. Presence of inflammation, active infection or skin disorder, such as 
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SYNOPSIS
eczema, rosacea, facial psoriasis, herpes zoster etc., near or in the 
treatment area.
14. Presence of cancerous or pre-cancerous lesions in the treatment area.
15. History of other facial treatment, surgery or other aesthetic procedures 
(e.g. ablative skin resurfacing, laser treatment, micro needling, chemical 
peel) in the previous 12 months that, in the investigator’s opinion, could 
interfere with study injections and/or assessments or expose the subject 
to undue risk by study participation.
16. Planned facial surgery, eye surgery (including LASIK procedure) or 
aesthetic procedures (e.g. ablative skin resurfacing, laser treatment, 
micro needling, chemical peel, botulinum toxin treatment, or dermal 
fillers) in the face during the study period.
17. History or presence of facial nerve palsy, or any medical condition that 
may put the subject at increased risk with exposure to botulinum toxin 
including diagnosed myasthenia gravis, Lambert-Eaton syndrome, 
amyotrophic lateral sclerosis, or any other condition that might interfere 
with neuromuscular function.
18. Use of medications that affect neuromuscular transmission such as 
curare-like 
depolarizing 
agents, 
lincosamides, 
polymyxins, 
anticholinesterases, and aminoglycoside antibiotics.
19. Subject with bleeding disorder or subject currently using anticoagulants.
20. Subject has any prior or current psychiatric illness (e.g. Psychosis, 
depression, anxiety), alcohol or drug abuse, or is taking antidepressant, 
anxiolytic, or antipsychotic medication that, in the investigator’s opinion, 
could affect the subject’s safety and/or participation in the study.
21. Other concurrent medical conditions, therapy, or other condition that, in 
the investigator’s opinion, would interfere with the evaluation of the study 
medication, safety or efficacy, and/or put the subject at risk if he/she 
participates to the study.
22. Participation in an investigational device or drug study within 30 days 
prior to study treatment or plans to enroll in any other investigational 
study during participation in this study.
23. Study center personnel, close relatives of the study center personnel 
(e.g. parents, children, siblings, or spouse), employees or close relatives 
of employees at the sponsor company.
Investigational Product:
QM1114-DP is a BoNT-A, supplied as a sterile, buffered solution for 
injection containing the drug substance (QM1114-DS).
Strength/Concentration:
100 U/ml
Dosage (total daily dose):
50 U total (0.5 mL)
10 U per injection point (0.1 mL per injection point)
Route:
Intramuscular injection
Dose regimen:
Single treatment at baseline visit
Location of treated area:
Glabellar region
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SYNOPSIS
Placebo Product:
The matching placebo for QM1114-DP is supplied as a sterile, buffered 
solution for injection, containing the excipients for the investigational 
product but without the drug substance (QM1114-DS).
Strength/Concentration:
N/A
Dosage (total daily dose):
0.5 mL total, 0.1 mL per injection point
Route:
Intramuscular injection
Dose regimen:
Single treatment at baseline visit
Location of treated area:
Glabellar region
Efficacy Assessments:

7-point 
Global 
Aesthetic Improvement 
Scale 
(GAIS)
(subject 
assessment)

Diary Card (subject assessment)
Study Objective:
The objectives of the study are to evaluate the aesthetic improvement and 
onset of QM1114-DP treatment effect in subjects with moderate to severe 
glabellar lines.
Primary Efficacy Objective 
and Endpoint:
1.
To demonstrate superiority in aesthetic improvement following a single 
dose of QM1114-DP compared to placebo as assessed by the subject 
using the GAIS at maximum frown at Month 1.
Endpoint: Responder rate based on the 7-point GAIS. A responder 
is defined as a subject who responds at least “Improved” on the 
GAIS at maximum frown.
Secondary Efficacy 
Objectives and Endpoints:
1.
To evaluate onset of treatment effect following a single dose of 
QM1114-DP and placebo as assessed by the subject using the diary 
card on Days 0 through 7 post-treatment.
Endpoint: Onset of effect is defined as the first day a subject answers 
“yes” to the diary question.
2.
To evaluate aesthetic improvement following a single dose of QM1114-
DP and placebo as assessed by the subject using the GAIS at maximum 
frown at all applicable post-treatment time points. 
Endpoint: Responder rate based on the 7-point GAIS.A responder is 
defined as a subject who responds at least “Improved” on the GAIS at 
maximum frown.
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SYNOPSIS
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SYNOPSIS
randomized and dispensed the investigational product, and will be 
analyzed according to the randomization scheme. The ITT population 
will be the primary population used for efficacy analysis.

The per protocol (PP) population is a subset of the ITT subjects who 
complete the Month 1 visit and have no protocol deviations that are 
considered to have a substantial impact on the primary efficacy 
outcome. 

The safety population includes all subjects who were administered the 
study product, and will be analyzed according to as-treated principle. All 
safety data will be summarized descriptively based on the safety 
population.
Sample Size:
Interim Analysis:
Not applicable.
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CLINICAL STUDY SCHEMATIC AND FLOW CHART
Table 1
Clinical Study Schematic
                          Screening
                          
                                         Baseline/Randomization to Treatment
                           
Group 1
Group 2
n= 90
n= 30
Treatment 
QM1114-DP 50 U
Placebo
Treatment Frequency
Single treatment at baseline visit
                              
                                     Follow-up Visits
                                   Days 1, 2, 3, 4
                                      Months 1, 3, 6, 7, 8, 9, 10, 11,12
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Figure 1
Study Flow Chart
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Visit
1 month = 4 weeks
All visit windows are calculated from 
Baseline/Day 0
Visit 1
Visit 2
Visit 3
Visit 4
Visit 5
Visit 6
Visit 7
Visit 8
Visit 9
Visits 10-14
Visit 15
Screening1
Day 0 
Baseline1
Day 1
Day 2
Day 3
Day 4
Month 1
Month 3
Month 6
Months 7-11
Month 12/
EOS/ET2
Window
(≤ 2 weeks
of Visit 2)
(5 days)
(5 days)
(5 days)
(5 days)
(5 days)
Abbreviations: 
EOS = End of Study; ET = Early Termination;
 GAIS = Global Aesthetic Improvement Scale; 
1.
Screening and baseline visits may be performed on the same day. If performed on the same day, study activities should only be completed once (i.e., UPT, subject and investigator GL severity assessments, focused physical exam, vital signs, 
and inclusion/exclusion criteria review).
2.
If the subject withdraws before the final visit the assessments at Month 12/EOS/ET should be completed, if possible. 
3.
Includes date of birth, gender, race, ethnicity, height, weight, Fitzpatrick skin type.
4.
For previous toxin treatments, capture; brand, area(s) treated, and date(s) on the previous medications/procedures form.
5.
Females of childbearing potential. 
6.
Post-baseline, events suggestive of remote spread of toxin are also considered while doing clinical evaluations based on the subject’s symptoms and signs. Directed questioning and examination will then be performed as appropriate.
7.
Performed pre-treatment.
8.
Vital signs include blood pressure, heart rate and respiratory rate. Vital signs are taken seated, after approximately 10 min rest. 
9.
Only at select sites.
10.
Performed pre- and post-treatment.
11.
Subject will make his/her assessment independently of the investigator’s assessment.
12.
Performed at month 9 only 
13.
Part 1 to be completed post-treatment at baseline (Visit 2) and Part 2 to be completed at Month 1 (Visit 7).
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Abbreviation/Term
Definition
Mg
Milligram
mL
Milliliter
mM
Millimoles
MTD
Maximum tolerated dose
N or n
Number
N/A
Not applicable
OC
Observed cases
OTC
Over-the-counter
PI
Principal investigator; qualified person responsible for conducting 
the study at a study site
PP
Per-protocol
PQC
Product quality complaint
PT
Preferred term
QA
Quality assurance
RA
Regulatory authority
Reference product
An investigational or marketed product (i.e. active control), or 
placebo, used as a comparator in a clinical study
SAE
Serious adverse event
SAP
Statistical analysis plan
SIN
Subject identification number
SOC
System organ class
SOP
Standard operating procedure
Sponsor File
Essential documents relating to a clinical study as defined in 
applicable GCP guidance document and maintained by the 
sponsor.
SLA
Subject Live Assessment
Study Files
The investigator file and the sponsor file
Study Products
The investigational product and the reference product under study
Study Site
The location(s) where the study-related activities are actually 
conducted
SUSAR
Suspected unexpected serious adverse reactions
TEAE
Treatment emergent adverse event
U
Unit
UPT
Urine pregnancy test
US
United States
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Abbreviation/Term
Definition
v/v
Volume/volume
WFI
Water for injection
WHO
World Health Organization
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1.
BACKGROUND AND RATIONALE
1.1
Medical Background and Short Rationale for the Clinical Study
Botulinum toxin (BoNT) is a potent neurotoxic protein produced by the Gram-positive 
anaerobic bacterium, Clostridium botulinum. The molecule is produced naturally by these 
bacteria together with a series of accessory proteins, forming what is termed the “toxin 
complex”. The neurotoxin is the cause of the severe and potentially fatal disease of botulism. 
In addition, the protein is used in very small quantities as a treatment modality for aesthetic 
and medical indications, many of which are characterized by increased muscle activity. 
Botulinum toxins occur in seven known serotypes (A-G) that are produced by different strains 
of Clostridium botulinum. Clinically important biologic activity is limited primarily to the 
A and B serotypes, of which the type A serotype (BoNT-A) is used widely throughout the 
world for the treatment of a range of clinical conditions.
BoNT-A blocks the release of acetylcholine into the neuromuscular junction (synapse) cleft, 
thereby prohibiting the activation of acetylcholine receptors. Paresis by chemical denervation 
thus occurs in the target muscle, leading to inhibition of muscular contraction. The active 
neurotoxin is 150 kilodalton (kDa) molecular weight and QM1114-DP only contains this part 
of the toxin complex: there are none of the other accessory proteins which are normally 
associated with the 150 kDa active moiety.
Since the 1970s, BoNT-A has been investigated and subsequently approved for the treatment 
of multiple indications around the world.2,3 Treatment of strabismus by relaxation of 
overactive extraocular muscles was the first reported medical use.4 Clinical studies for 
aesthetic indications were first performed in the late 1980s.5 Since then, many other clinical 
indications have been investigated,6-8 although the number of approved indications is much 
smaller. BoNT-A products have been licensed in the US for the aesthetic indications of 
glabellar lines (GL), lateral canthal lines (LCL) and forehead lines (FL), together with 
therapeutic indications such as strabismus, blepharospasm, hemifacial spasm, cervical 
dystonia, focal spasticity, prophylactic treatment of chronic migraine, overactive bladder and 
hyperhidrosis. 
In the early 1990s, patients treated with BoNT-A for blepharospasm were observed to lose 
their frown lines and, 5,9 since publishing these observations, the use of BoNT-A in the 
aesthetic setting has accelerated. Injectable BoNT-A products have been investigated for 
multiple aesthetic indications in attempts to reverse the appearance of aging, especially in the 
facial region.2 In the treatment of facial lines, the effect of BoNT-A injections usually persists 
for approximately 4-6 months. Facial muscle activity and severity of the facial wrinkles then 
returns to baseline. Full functionality of facial muscles is usually restored by approximately 
6 months post-treatment.10
There are four BoNT-A products currently licensed in the US for the treatment of GL in adults 
(Botox Cosmetic®, Dysport®, Xeomin®, and JeuveauTM). QM1114-DP is a novel botulinum 
toxin type-A1 which is presented as a liquid formulation. Unlike the main commercially 
available botulinum toxins in the United States (US), QM1114-DP is manufactured and 
formulated without any animal or human proteins.  As a novel BoNT-A with a differentiated 
formulation, QM1114-DP is being developed for the treatment of moderate to severe GL in 
adults over 18 years.
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1.2.3
Clinical Documentation
Following successful completion of clinical study 
, a randomized, double-
blind, placebo controlled, dose finding study of QM1114-DP using three different single doses 
of QM1114-DP (30, 45, 60 U) in male or female subjects aged over 18 years with moderate to 
very severe GL was performed.
Efficacy in reduction of GL severity was evaluated using the 5-point MAS scale. Efficacy 
assessments were made for up to and including six months post-treatment.
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No additional risks specific to the QM1114-DP 50 U dose are anticipated, and sufficient 
clinical experience with BoNT-A products with similar mode of action for facial aesthetic use 
at dose levels corresponding to the dose levels in this study demonstrate the potential benefit 
of the proposed treatments. Adverse events will be recorded at each study visit, and subjects 
will also be queried for any potential signs and symptoms of local and remote spread of the 
toxin effect.
In conclusion, given the anticipated low level of transient and acceptable risks, the risk/benefit 
assessment of the use of QM1114-DP to assess aesthetic improvement and onset of treatment 
effect in subjects with moderate to severe GL appears to offer a substantial clinical benefit at 
reasonable risk.
Due to the COVID-19 pandemic, the feasibility and immediate necessity of starting a new 
clinical trial should be critically assessed and additional risks to trial participants should be 
addressed. Thus, a risk benefit assessment of the impact of COVID-19 potentially affecting 
trial participants and COVID-19 related measures affecting clinical trial conduct will be 
performed before the study starts to decide if the study can start or if it needs to be postponed.
If the conclusion of the assessment is that the risk benefit is currently negative the study will 
not start until the outbreak is under control with a substantially reduced risk for subjects being 
infected by COVID-19, as guided by relevant research and local and international health 
authorities’ guidelines and regulations. Measures to minimize the risk of exposure to 
COVID-19 for study subjects include, but is not limited to, replacing site visits with telephone 
call visits, replacing live assessments with remote digital assessments, postponing site visits 
and cancellation of site visits not needed for evaluation of the primary endpoint.
2.
CLINICAL STUDY OBJECTIVES, ENDPOINTS, AND CLINICAL 
HYPOTHESIS
2.1
Clinical Study Objectives
The objectives of the study are to evaluate the aesthetic improvement and onset of QM1114-DP 
treatment effect in subjects with moderate to severe glabellar lines.
2.1.1
Primary Efficacy Objective and Endpoint
The primary efficacy objective is to demonstrate superiority in aesthetic improvement 
following a single dose of QM1114-DP compared to placebo as assessed by the subject using 
the Global Aesthetic Improvement Scale (GAIS) at maximum frown at Month 1.
For primary endpoint the responder rate will be based on the 7-point GAIS. A responder is 
defined as a subject who responds at least “Improved” on the GAIS at maximum frown.
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2.1.2
Secondary Efficacy Objectives and Endpoints
The secondary efficacy objectives and endpoints of the study are:
1. To evaluate onset of treatment effect following a single dose of QM1114-DP and placebo 
as assessed by the subject using the diary card on Days 0 through 7 post-treatment.
Endpoint: Onset of effect is defined as the first day a subject answers “yes” to the diary 
question.
2. To evaluate aesthetic improvement following a single dose of QM1114-DP and placebo as 
assessed by the subject using the GAIS at maximum frown at all applicable time points. 
Endpoint: Responder rate based on the 7-point GAIS. A responder is defined as a subject 
who responds at least “Improved” on the GAIS at maximum frown.
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2.1.4
Safety Objectives and Endpoints
The safety objective is to evaluate the safety of a single dose of 50U of QM1114-DP and 
placebo in the treatment of moderate to severe GL.
Endpoints:

Incidence and severity of treatment emergent AEs (TEAEs)

FPE findings

Vital signs

Neutralizing antibody production
2.2
Clinical Hypothesis
The clinical hypothesis of the study is that QM1114-DP will demonstrate a higher rate of
aesthetic improvement and has an earlier onset of treatment effect compared to placebo in 
subjects with moderate to severe GL, and has an acceptable safety profile.
3.
OVERALL CLINICAL STUDY DESCRIPTION
This is a multi-center, randomized, double-blind, placebo-controlled study to assessed aesthetic 
improvement and onset of QM1114-DP treatment effect in subjects with moderate to severe 
GL.
Following the informed consent and screening process, eligible subjects will be randomly 
assigned in a 3:1 ratio to receive a single treatment at baseline (Day 0) of 50 U of 
QM1114-DP (90 subjects) or placebo (30 subjects) in the glabellar region.
Following treatment at baseline, subjects will be monitored for safety and efficacy according 
to the Schedule of Assessments for 12 months.
4.
CLINICAL STUDY DURATION AND TERMINATION
The planned duration of recruitment (from first subject first visit [FSFV] to last subject first 
visit [LSFV]) is approximately 2 months.
The planned clinical study duration from FSFV to last subject last visit (LSLV) is 
approximately 14.5 months.
Clinical study participation for each subject is approximately 12.5 months.
The sponsor may decide to prematurely terminate or suspend the participation of a particular 
clinical study center (for example, lack of subject enrollment or non-compliance with clinical 
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study protocol, regulation, or Good Clinical Practice [GCP]) or prematurely suspend the 
clinical study (for example, for safety, study products(s) quality, regulatory, efficacy, or 
logistical reasons) at any time with appropriate notification.
5.
SELECTION AND DISPOSITION OF CLINICAL STUDY POPULATION
5.1
Number of Subjects
As a screen failure rate of approximately 10% is anticipated, approximately 134 subjects will 
be screened in order to get 120 subjects enrolled in a 3:1 ratio to QM1114-DP 50 U (N=90) or 
placebo (N=30). It is expected that each center will recruit a similar number of subjects.
5.2
Clinical Study Population Characteristics
In order to be eligible for the clinical study, subjects must fulfill all of the following criteria. 
These criteria are applicable at both screening and baseline unless otherwise specified. 
5.2.1
Inclusion Criteria
1. Male or female, 18 years of age or older.
2.
3.
4. Previous repeated treatments with BoNT-A products for aesthetic use within 3 years prior 
to the screening visit.
5. Female of non-childbearing potential (i.e., post-menopausal [absence of menstrual 
bleeding for 1 year prior to screening, without any other medical reason], or has 
undergone hysterectomy or bilateral oophorectomy).
OR
Female of childbearing potential with a negative urine pregnancy test at screening and 
baseline, and agrees to use a highly effective and approved contraceptive method for the 
duration of the study. A highly effective method of contraception is defined as:

Bilateral tubal ligation;

Combined (estrogen and progesterone containing) oral, intravaginal or transdermal 
contraceptives that inhibit ovulation as the primary mode of action, on a stable dose 
for at least 28 days prior to screening visit;

Intrauterine device (IUD) inserted at least 28 days prior to screening visit;

Intrauterine hormone-releasing system;

Partner vasectomized for at least three months prior to screening visit;
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
Progestogen-only oral, injectable or implantable contraceptives that inhibit ovulation 
as the primary mode of action, on a stable dose for at least 28 days prior to screening 
visit; or

Strict abstinence (i.e., refraining from heterosexual intercourse for the duration of the 
subject’s participation in the study).
6. Time and ability to complete the study and comply with instructions.
7. Understands the study requirements and signed the informed consent form (ICF).
5.2.2
Exclusion Criteria
1. Previous use of any botulinum toxin in facial areas within 9 months prior to study 
treatment.
2. Anticipated need for treatment with botulinum toxin of any serotype for any reason 
during the study (other than the investigational product).
3. Female who is pregnant, breast feeding, or intends to conceive a child during the study.
4. Known allergy or hypersensitivity to any component of the investigational product 
(QM1114-DP) or any botulinum toxin serotype.
5. Inability to substantially lessen GL by physically spreading them apart, as determined 
by the investigator.
6. Clinically significant abnormal focused physical exam finding(s) at screening or 
baseline visits, in the investigator’s opinion.
7. Excessive skin laxity in the treatment area or periorbital area.
8. Previous use of any hyaluronic acid soft tissue augmentation therapy in the glabella 
area within 6 months before baseline.
9. Previous soft tissue augmentation with any permanent (non-biodegradable such as 
silicone, polyacrylamide, etc.) or semi-permanent (i.e., calcium hydroxylapatite, poly-
L-Lactic acid or polymethyl-methacrylate) product; lifting threads, or autologous fat in 
the treatment area.
10. History, presence, or predisposition of eyelid or eyebrow ptosis (heavy eyebrows), 
amblyopia (i.e., lazy eye), or previous surgery around the eye that may lead to the above 
events, as determined by the investigator.
11. Marked facial asymmetry, excessive dermatochalasis (i.e., excess of skin in eyelids), 
or marked periocular or eyebrow asymmetry.
12. Presence of scar(s), piercing(s), or tattoo(s) (including microblading of eyebrow or 
eyeliner) in the treatment area or around the treatment area that, in the investigator's 
opinion, may interfere with study evaluations.
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13. Presence of inflammation, active infection or skin disorder, such as eczema, rosacea, 
facial psoriasis, herpes zoster etc., near or in the treatment area.
14. Presence of cancerous or pre-cancerous lesions in the treatment area.
15. History of other facial treatment, surgery or other aesthetic procedures (e.g. ablative 
skin resurfacing, laser treatment, micro needling, chemical peel) in the previous 12 
months that, in the investigator's opinion, could interfere with study injections and/or 
assessments or expose the subject to undue risk by study participation.
16. Planned facial surgery, eye surgery (including LASIK procedure) or aesthetic 
procedures (e.g. ablative skin resurfacing, laser treatment, micro needling, chemical 
peel, botulinum toxin treatment, or dermal fillers) in the face during the study period.
17. History or presence of facial nerve palsy, or any medical condition that may put the 
subject at increased risk with exposure to botulinum toxin including diagnosed 
myasthenia gravis, Lambert-Eaton syndrome, amyotrophic lateral sclerosis, or any 
other condition that might interfere with neuromuscular function.
18. Use of medications that affect neuromuscular transmission such as curare-like 
depolarizing 
agents, 
lincosamides, 
polymyxins, 
anticholinesterases, 
and 
aminoglycoside antibiotics.
19. Subject with bleeding disorder or subject currently using anticoagulants.
20. Subject has any prior or current psychiatric illness (e.g. Psychosis, depression, anxiety), 
alcohol or drug abuse, or is taking antidepressant, anxiolytic, or antipsychotic 
medication that, in the investigator's opinion, could affect the subject's safety and/or 
participation in the study.
21. Other concurrent medical conditions, therapy, or other condition that, in the 
investigator's opinion, would interfere with the evaluation of the study medication, 
safety or efficacy, and/or put the subject at risk if he/she participates to the study.
22. Participation in an investigational device or drug study within 30 days prior to study 
treatment or plans to enroll in any other investigational study during participation in 
this study.
23. Study center personnel, close relatives of the study center personnel (e.g. parents, 
children, siblings, or spouse), employees or close relatives of employees at the sponsor 
company.
5.3
Medical History
Relevant history of surgical events and medical conditions shall be documented in the subject’s 
study file and electronic case report form (eCRF) using medical terminology.
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5.4
Previous and Concomitant Therapies
5.4.1
Definition
Previous therapies are defined as therapies that have been stopped within 4 weeks preceding 
the screening visit or within timeframes specified in the inclusion/exclusion criteria.
Concomitant therapies are defined as follows:

any existing therapies ongoing at the time of the screening visit,

any changes to existing therapies (such as changes in dose or formulation) during the 
course of the clinical study, or

any new therapies received by the subject since the screening visit.  
5.4.2
Categories
The following two categories are to be considered for previous and concomitant therapies: 

Drugs including but not limited to, prescription, over-the-counter (OTC), birth control 
pills/patches/hormonal 
devices, 
vitamins, 
herbal 
medicines/supplements, 
and 
homeopathic preparations.

Medical and surgical procedures including, but not limited to, laser/radiation procedures, 
dermal fillers (area of treatment should be indicated), X-rays, surgeries, tooth extractions.
5.4.3
Recording
Previous and concomitant therapies are to be recorded in the subject’s source documents and 
eCRFs.
Concomitant therapies are to be reviewed at each visit and updated in the source documents 
and eCRFs as needed. 
Any new concomitant therapy or modification of an existing therapy may be linked to an 
adverse event (AE).  A corresponding AE form should be completed to account for the change 
in therapy, except in some cases such as therapy used for prophylaxis, dose modification for a 
chronic condition, etc.
5.4.4
Authorized Concomitant Therapies
Unless listed in prohibited concomitant therapies (see Section 5.4.5), all are authorized.
5.4.5
Prohibited Concomitant Therapies
The following therapies are prohibited because they may interfere with the efficacy and/or 
safety assessment of the study products(s):

Botulinum toxin of any serotype.

Any other investigational new drug or device.
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
Any absorbable (temporary) or non-absorbable (permanent) material in the treatment 
area.

Facial aesthetic procedures (e.g., ablative skin resurfacing, laser treatment, micro 
needling, photodynamic therapy, tattooing or chemical peel) or any other procedures in 
the treatment area.

Facial surgery or eye surgery (including LASIK procedure).

Medications that affect neuromuscular transmission such as curare-like depolarizing 
agents, lincosamides, polymyxins, anticholinesterases and aminoglycoside antibiotics.
If a prohibited therapy becomes a necessary treatment for best clinical interest of the subject or 
due to safety reason, the Medical Monitor (Section 11.9) should be notified, if time permits, to 
discuss possible alternatives prior to administration of a prohibited therapy.
If a subject receives a prohibited therapy during the clinical study, the Medical Monitor 
(Section 11.9) should be notified to discuss the subject’s continuation in the clinical study.
5.5
Procedures/Reasons for Subject Discontinuation
An investigator may decide to discontinue a subject from the clinical study for safety reasons.
Although the importance of completing the entire clinical study should be explained to the 
subject by the clinical study personnel, any subject is free to discontinue participation in this 
clinical study at any time and for whatever reason, specified or unspecified, and without any 
prejudice.  No constraints are to be imposed on the subject, and when appropriate, a subject 
may be treated with other conventional therapy when clinically indicated. 
When a subject does not complete the clinical study, he/she will be fully assessed, if such 
assessment is possible.  The procedures designated for the Month 12/ Early Termination (ET) 
visit should be completed for all subjects discontinuing the clinical study and the appropriate 
eCRF should be completed.
All discontinuations and the reason for discontinuation are to be documented by the 
investigator on the exit form. For discontinuation due to an AE, the AE form is to be completed. 
The investigator should also ensure that the subject receives suitable therapy for the AE.
Potential reasons for discontinuation are listed below:

Adverse Event:
Complete an AE form.

Withdrawal by Subject:
Includes consent withdrawal, subject relocation, schedule 
conflicts, etc.  Explain the reason for withdrawal in the 
comment section of the eCRF exit form.

Lost to Follow-up:
Confirmed with two documented phone calls and a certified 
letter (delivery receipt requested) without answer.  Explain in 
the comment section of the eCRF exit form.
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
Other:
This category is to be used for a subject who discontinues due 
to a reason other than as specified in the predefined categories 
above.  Explain the reason for discontinuation in the comment 
section of the eCRF exit form.
A subject who has been randomized and assigned a kit number/randomization number cannot 
be replaced by another subject if he/she discontinues the clinical study for any reason. 
Additional subjects could be enrolled (randomized/assigned to treatment) in order to attain the 
number of evaluable subjects.
Pregnancies occurring during the screening period are considered screen failures; they should 
be recorded as such in the eCRF and no pregnancy form is to be completed. In case of a 
pregnancy occurring after the baseline visit, follow the procedures described in 
Section 7.2.4.2.3. The subject may remain in the study, but no invasive procedure should be 
conducted (e.g. no sample taken for lab test).
The sponsor may also decide to prematurely terminate or suspend a subject’s participation in 
the clinical study.
6.
CLINICAL SUPPLIES
Details of the drug composition and excipients are provided in the current QM1114-DP IB.12
6.1
Clinical Supply Identification and Use
6.1.1
QM1114-DP
The investigational product (QM1114-DP) will be supplied as a sterile solution for injection 
containing the drug substance, QM1114-DS.  The drug substance is a BoNT Type A. 
QM1114-DS is diluted in a buffer solution.  
At the baseline visit, a total volume of 0.5 mL of QM1114-DP will be administered in 5 equal 
aliquots of 0.1 mL each per the blinded randomization assignment.
6.1.2
Placebo
Placebo will be supplied as a buffered solution for injection containing only the buffer solution
of QM1114-DP; placebo does not contain active drug substance.
At the baseline visit, a total volume of 0.5 mL of placebo will be administered in 5 equal 
aliquots of 0.1 mL each per the blinded randomization assignment.
The placebo product should be stored at the recommended temperature (between 2°C and 8°C, 
36 ºF – 46 ºF). The placebo product should not be frozen and should be protected from light.
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6.1.3
Study Products(s) Description
Table 3
Description and Usage of the Study Products(s)
Investigational product
Reference product
Name of drug substance  
QM1114-DS
N/A
Internal Code
QM1114-DP
Placebo
Pharmaceutical Form
Solution for injection
Solution for injection
Concentration
100 U/mL, buffered solution
N/A, buffer solution
Buffer composition
Packaging
Glass vial. Fill volume 1.5 mL
Glass vial. Fill volume 1.5 mL
Dosage
50 U
0.5 mL total
0.1 mL per injection point
N/A
0.5 mL total
0.1 mL per injection point
Route
Intramuscular injection
Intramuscular injection
Dose regimen 
Single treatment at baseline visit
Single treatment at baseline visit
Location of treated area
Glabellar region
Glabellar region
6.1.4
Subject Identification Number 
Each study participant who has signed the Informed Consent Form (ICF) will be entered into 
the eCRF system and a subject identification number (SIN) will be assigned via the eCRF 
system. For the duration of the study, the subject will be identified using the subject number 
for all documentation and discussion.
Subject numbers will consist of the study center number followed by a consecutive number 
starting with 001 at each center. The subject numbers shall be allocated in ascending sequential 
order within each center. If a subject is deemed not eligible for the study participation, the 
reason for screen failure should be specified. A screen failure cannot be re-screened.
A log/listing should be maintained by each site for all subjects who have signed the ICF. There 
should be sufficient information to link the eCRF to a study subject’s source documents and 
medical records.
6.1.5
Method of Treatment Assignment
Before starting the study, a randomization list stratified by study center will be generated.
When the investigator has confirmed subject eligibility, the subject will be allocated a study 
product within the electronic data capture (EDC) system. 
6.1.6
Kit Number/Randomization Number
A kit number/randomization number, a unique number on the label of the study products, will 
be assigned to each eligible subject at baseline.
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Kit number/randomization number will be allocated in ascending sequential order to each 
eligible subject.
6.1.7
Instructions for Use and Administration
QM1114-DP (50 U) will be compared to placebo in this study and administered based on 
randomization.
Placebo is identical in appearance to the active QM1114-DP but contains no active drug 
substance.
QM1114-DP and placebo are administered in exactly the same way. All treating investigators 
will be trained in the administration technique prior to the study start.  
Handling of accidently damaged or spilled study product is described in the Material Safety 
Data Sheet.
See also QM1114-DP IB. 12
6.1.7.1
Treatment Procedure
Prior to injection, the treatment area should be cleaned with a suitable antiseptic solution. An 
appropriately sized syringe and needle (e.g., 30-33 gauge needle) should be used to administer 
treatment.
At baseline, subjects will be randomized to receive treatment with QM1114-DP or placebo.  
Each treatment includes five intramuscular (IM) injections of equal volume (0.1 mL) 
administered at 5 injection sites in the glabellar region (0.5 mL in total).  The injections should 
commence in the procerus muscle followed by the corrugator supercilii muscles on each side, 
moving outwards from the median. All injections should be approximately 1 cm above the 
upper orbital rim and internal to the mid-pupillary lines (Figure 2).
In order to minimize risks of regional effect of the neurotoxin (e.g., eyelid ptosis), the 
investigator should use one thumb to apply pressure on the upper orbital rim while injecting. It 
is recommended that injection is not closer than 1 cm above the central eyebrow or the bony
supraorbital ridge.  Moreover, the tip and bevel of the needle should always be pointed away 
from the study subject.
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Figure 2
Injection Sites for Treating Glabellar Lines
6.1.7.2
Post-treatment Care
Following treatment administration, subjects will be monitored at the study center for 30 
minutes. 
Subjects will be instructed to avoid applying pressure, rubbing or massaging the treated area, 
or lying face down for 4 hours after treatment.
6.1.7.3
Treatment Regimen
Each subject will receive a single treatment with QM1114-DP or placebo at the baseline visit.
The treatments investigated in this study are:

50 U of QM1114-DP (0.5 mL total injection volume/0.1 mL per injection point)

Placebo
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6.3
Supplies Management
6.3.1
Accountability
Upon receipt of the study product(s), the investigator or designee will maintain accurate records 
of the study product(s) delivery to the clinical study center, the inventory at the clinical study 
center, the use by each subject, the reconciliation of all study product(s) received from the 
sponsor’s designee, and the return to the sponsor’s designee for disposal of unused study 
product(s).
All study product(s) sent to the investigator/institution will be accounted for and no 
unauthorized use is permitted.
6.3.2
Storage of Study Product(s)
Study product(s) must be stored in a safe and secure area with restricted access, under the 
storage conditions specified by the sponsor (see Table 3).
6.3.3
Dispensing and Return 
All study product(s) must be inventoried and a record of the dispensing for each subject must 
be appropriately documented. Any dispensing errors must be reported to the sponsor/contract 
research organization (CRO) and properly documented.
In the event of early termination/suspension of the clinical study, a rapid recall of study 
product(s) will be initiated.  
Unused or expired study product will be returned for destruction to the sponsor representative 
at time points approved by the sponsor.
6.3.4
Treatment Compliance Management and Record
The treatment is an injection administered by the investigator. Details of the injection 
procedure will be recorded in the eCRF and subject source documents. No other measurements 
of treatment compliance will be made.
6.3.5
Dose Modification 
Dose modifications are not permitted.
6.3.6
Product Quality Complaints
Product Quality complaints (PQCs) should be reported to the Safety e-mail listed in 
Section 11.9. A PQC is an external judgement presuming a quality defect of a product; quality 
issue for a product relating to its presentation or use, identified by a subject, a practitioner or 
investigator site personnel, a distributor, or anyone else involved in clinical supplies handling. 
Examples may include but are not limited to appearance issues, odor, damaged stoppers, low 
fills, and foreign matter in the product. These complaints may or may not represent a potential 
risk to the subject. A PQC form must be completed by the study center personnel and forwarded 
to the sponsor or designee within 24 hours of awareness. Affected study product should be 
quarantined, and not used, until further notice by the sponsor.
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Additional contact details are provided in the investigator’s site file.
6.4
Blinding
This is a double-blind study in which neither the investigator, sub-investigator, study staff, nor 
the subject will know the subject's study product assignment (i.e., QM1114-DP or placebo). 
Placebo is identical in appearance to QM1114-DP but contains no active drug substance.
Subjects will be randomized at baseline to either treatment with QM1114-DP or placebo. In 
order to maintain the blind, the study products, QM1114-DP and placebo, will be supplied in 
identical vials, each with a unique number on the vial label. Both QM1114-DP and placebo 
will be administered in exactly the same way.
An un-blinded statistician will generate the randomization schedule; however, he/she will not 
be involved in any other aspect of the study prior to database lock.
The sponsor’s staff or designees directly involved in clinical operations management, data 
management, and statistical evaluation of the study will remain blinded until the database is 
locked, unless emergency unblinding is required. 
6.4.1
Verification of Blinding
The sponsor’s staff or designees will assess and verify maintenance of the study blind during 
the study through routine monitoring visits. 
6.4.2
Unblinding During the Clinical Study
Emergency un-blinding during the clinical study may be required for therapeutic or for 
regulatory reasons (for expedited safety reporting).
A blind-break system will be available for investigators.  In such an emergency, the 
investigator will only break the blind for the subject involved.
The investigator must notify the sponsor immediately in the event of such an emergency (see 
contact details in Section 7.2.4.2.2).  If possible, the investigator should notify the sponsor 
before breaking the blind in order to discuss this decision with the sponsor.  The investigator 
is required to document each case of emergency unblinding and inform the sponsor 
immediately.
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7.
CLINICAL STUDY ASSESSMENTS
7.1
Efficacy Assessments
7.1.1
Global Aesthetic Improvement Scale 
Subjects will rate the global aesthetic improvement of their GL at maximum frown, relative to 
their pre-treatment appearance, using the following categorical scale at all post-treatment time 
points through Month 12.
Rating
Very Much Improved
Much Improved
Improved
No Change
Worse
Much Worse
Very Much Worse
Subjects will be asked: 
“How would you rate the change in appearance of your glabellar lines (lines between your 
eyebrows) at maximum frown compared with immediately before the injection?” 
Subjects will be instructed to select the one rating that best describes the degree to which the 
appearance of their GLs at maximum frown has changed relative to baseline.  The subject may 
review the baseline photograph to aid in the assessment. 
7.1.2
Subject Diary Card
Subjects will be asked to record their assessment of study treatment response in a diary card on 
Days 0 through 7 post-treatment. They will be asked to respond “yes” or “no” to the following 
question: 
“Since being injected have you noticed an improvement in the appearance of your glabellar 
lines (lines between your eyebrows) when you frown?” 
Subjects are to complete the diary card daily, starting on the day of treatment (Day 0), and 
return the diary to study center at their Month 1 visit. 
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7.2
Safety Assessments
Safety assessments will be conducted for all subjects at the time points indicated in Schedule 
of Assessments (Table 2).  Safety parameters include an evaluation of AEs, focused physical 
examination, vital signs, and neutralizing antibody production.
7.2.1
Focused Physical Examination (FPE)
At the time points indicated in the Schedule of Assessments (Table 2), the investigator or 
designee will perform a FPE of the subject that includes the face, head, and neck. Further details 
are provided in Appendix 7.
Post-baseline, the signs and symptoms will also be monitored via FPE of face, head, and neck 
to evaluate local effect of toxin. In addition, a general physical examination to evaluate the 
remote spread events will be conducted. The list of remote spread of toxin events is considered 
while doing clinical evaluations based on subject’s symptoms and signs (Appendix 8). Directed
questioning and examination will then be performed as appropriate.
The investigator may choose to investigate any other sign that he/she observes during the 
physical examination. Clinically significant abnormalities noted pre-injection, i.e., at the 
screening/baseline visits, should be recorded as medical history and assessed as to whether the 
abnormalities affect subject eligibility. Clinically significant abnormalities noted post-injection 
should be recorded as AEs.
7.2.2
Vital Signs
Evaluation of vital signs shall be performed after approximately 10 minutes rest in the sitting 
position. It shall include measurement of systolic and diastolic blood pressure, heart rate, and 
respiratory rate. 
All abnormal values at the baseline visit identified as clinically significant by the investigator 
shall be recorded in the Medical History form.
For any clinically significant changes from the baseline visit, an AE is to be recorded.
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7.2.3
Neutralizing Antibody Testing
Subjects will have blood samples taken at baseline prior to treatment, Month 1, and Month 6
for measurement of serum neutralizing antibody testing against QM1114-DP. Additional 
information and detailed description of sample volumes, processing, and storage requirement 
will be included in a Laboratory Manual.
7.2.4
Adverse Events
AEs are to be monitored throughout the course of the clinical study from the time the informed 
consent form has been signed. All AEs are to be reported on the AE form of the eCRF with 
complete information as required. 
If AEs occur, the main concern shall be the safety of the subjects. At the time of the ICF 
signature, each subject must be provided with the name and phone number of clinical study 
center personnel for reporting AEs and medical emergencies.
At each post enrollment visit, the investigator (or sub-investigator) will question the subject 
about AEs using an open non-persuasive question to elicit reporting of AEs, for example “Have 
you noticed any change in your health since the last visit?”  Additional questioning and 
examination will then be performed as appropriate.
7.2.4.1
Definitions
7.2.4.1.1
Adverse Events 
According to International Council for Harmonisation (ICH) E2A,15 an AE is any untoward 
medical occurrence in a patient or a clinical investigation subject administered a 
pharmaceutical product and which does not necessarily have a causal relationship with this 
treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
(investigational) product, whether or not related to the medicinal (investigational) product.
Thus, any new sign, symptom or disease, or any clinically significant worsening of an existing 
sign, symptom or disease (including new episodes of a chronic disease [e.g., hay fever, allergy]) 
compared to the condition at the first visit, should be considered as an AE. Lack of efficacy is 
not considered as an AE.
Notes:

There should be an attempt to report a diagnosis rather than the signs, symptoms or 
abnormal laboratory values associated with the report of an AE. However, a diagnosis 
should be reported only if, in the investigator’s judgment, it is relatively certain. 
Otherwise, symptoms, signs, or laboratory values should be used to describe the AE.

Pregnancy is not to be considered as an AE; however, is an important medical event that 
must be monitored as described in Section 7.2.4.2.3.
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
The effects of all BoNT products may spread from the area of injection to produce 
symptoms consistent with BoNT effects. These symptoms have been reported hours to 
weeks after injection. Remote spread of toxin that affects swallowing and breathing can 
be life threatening, and there have been reports of death. The risk of symptoms is 
increased in subjects who have underlying conditions (e.g. disorders of the 
neuromuscular junction) that would predispose them to these symptoms. BoNT is 
contraindicated in individuals with known hypersensitivity to any BoNT preparation or 
to any of the components in the formulation. 
7.2.4.1.2
Treatment Emergent Adverse Event 
A TEAE is an event that emerges during or after treatment, having been absent pre-treatment, 
or worsens relative to the pre-treatment state.
7.2.4.1.3
Serious Adverse Events 
A SAE is any untoward medical occurrence that at any dose:

Results in death,

Is life-threatening,

Requires inpatient hospitalization or prolongation of existing hospitalization,

Results in persistent or significant disability/incapacity, or

Is a congenital anomaly/birth defect.
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered an SAE when, based upon appropriate medical judgment, 
they may jeopardize the safety of the subject, and 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 dyscrasia, or 
convulsions that do not result in hospitalization.
Note: The term “life-threatening” refers to an event in which the subject was at risk of death at 
the time of the event; it does not refer to an event which hypothetically might have caused 
death if it were more severe.
Inpatient hospitalization is considered to have occurred if the subject has had to stay for a night 
at the hospital.  The criterion for prolongation of hospitalization is also defined as an extra night 
at the hospital.  Hospitalization may not constitute sufficient grounds to be considered as an 
SAE if it is solely for the purpose of a diagnostic test(s) (even if related to an AE), elective 
hospitalization for an intervention that was already planned before subject enrolment in the 
clinical study, admission to a day-care facility, social admission (e.g., if the subject has no place 
to sleep), or administrative admission (e.g., for a yearly examination).
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7.2.4.1.4
Unexpected Adverse Drug Reaction
An unexpected adverse drug reaction is defined as an adverse reaction, the nature or severity 
of which is not consistent with the applicable study product information (e.g., IB for an 
unapproved investigational product).
7.2.4.1.5
Adverse Event Reporting Period
The clinical study period during which AEs must be reported is the period from when the 
subject signed the ICF to the end of the subject’s participation.
The sponsor should be informed if the investigator becomes aware of any unusual safety 
information or any safety information that appears to be drug-related involving a subject who 
has participated in a clinical study, even after a subject has completed the clinical study.  
7.2.4.1.6
Severity
Severity is a clinical determination of the intensity of an AE and not the severity of a disease.
The investigator is to classify the intensity of AEs using the following definitions as a guideline.  
For this classification, the investigator will take into account the possible range of the intensity 
of the event and report the grade of intensity which is the most appropriate according to his/her
medical judgment.
Mild
Awareness of signs or symptom, but easily tolerated.
Moderate
Discomfort, enough to cause interference with usual activity.
Severe
Incapacitating with inability to work or perform usual activity.
7.2.4.1.7
Relationship to the Study Product and/or Clinical Study Procedure
The investigator is to determine whether there is a reasonable causal relationship between the 
occurrence of the AE and exposure to the study product and/or clinical study procedure.
Medical judgment should be used to determine the relationship, considering all relevant factors 
including the pattern of reaction, temporal relationships, relevant medical history, and 
confounding factors such as co-medication or concurrent diseases.
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The expression “reasonable causal relationship” is meant to convey in general that there are 
facts or arguments to suggest a causal relationship (ICH E2A, Section IIIA 1).
The relationship assessment for an AE is to be completed using the following definitions as a 
guideline:
Reasonable Possibility: According to the reporting investigator, there is a reasonable 
possibility (i.e., suggestive evidence or arguments) that there is a causal relationship 
irrespective of the dose administered between:

The study product (active or placebo) and the AE.

The clinical study protocol procedure (e.g., bruising or marks from blood draws, injection 
related trauma, etc.) and the AE.
A two-point scale (Yes or No response) shall be used for the causality assessment. The 
investigator shall be asked to indicate a response to each of the following questions in the 
eCRF:

“Do you consider that there is a reasonable possibility that the event may have been 
caused by the study product?”, and 

“Do you consider that there is a reasonable possibility that the event may have been 
caused by the study product injection procedure?”
If any of these questions is answered Yes, the AE is considered related. 
No Reasonable Possibility: No suggestive evidence or arguments can be identified regarding 
a causal relationship between the study product or the clinical study protocol procedure and the 
AE.
7.2.4.2
Reporting Procedures
7.2.4.2.1
Procedures for Reporting Adverse Events
The collection of AEs is from the time that a subject signs the ICF to their final visit.
At each post-enrollment visit, the investigator (or sub-investigator) will question the subject 
about AEs using an open non-persuasive question to elicit reporting of AEs, for example “Have 
you noticed any change in your health since the last visit?”  Directed questioning and 
examination will then be performed as appropriate. 
Any AE occurring during the AE reporting period, whether it is related to the study product or 
not, will be recorded immediately in the source document, and described on the AE form of 
the eCRF along with the date of onset, severity, relationship to the study product, action taken, 
and outcome, without omitting any requested and known information.  Additional information 
will be requested under certain circumstances.  
At study end, AEs assessed as related to the treatment or study procedure will be monitored
until they have resolved or reached a stable condition.  Other AEs will be monitored until the 
last visit if they have not resolved or reached a stable condition. 
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The investigator will maintain all pertinent medical records in the subject’s study file.  If 
necessary and approved by the subject or their legal health care representative, the investigator 
may contact the subject’s personal physician or other health care provider(s) to obtain further 
details.
For SAEs (see Section 7.2.4.2.2) and pregnancies (see Section 7.2.4.2.3), the sponsor is to be 
informed immediately by e-mail.  The event must be reported to the Safety e-mail within 
24 hours of receipt of the information (contact details in Section 11.9).
7.2.4.2.2
Procedure for Reporting a Serious Adverse Event
For a SAE occurring during the clinical study, regardless of whether it is related to the treatment 
or not, and of whether it is expected or not, the investigator must do the following:
1.
Take prompt and appropriate medical action, if necessary.  The safety of the subject is 
the first priority.
2.
Ensure that the event is classified as an SAE (Section 7.2.4.1.3).
3.
Complete the AE form provided in the eCRF as fully as possible.
Print and complete the SAE form.  The completed form, accompanied by any other 
relevant information or anonymized medical records (e.g., laboratory test results) within 
24 hours of receipt of the information to Safety e-mail listed below. The demographics, 
medical history, drugs/therapies form, medical and surgical procedures form, and AE 
pages of the eCRF must be completed and available for review in the EDC system at the 
time of the report.
4.
Immediately send the completed SAE report form to the Safety e-mail and discuss further 
actions to be taken.
E-mail: 
Additional contact details are provided in the investigator’s site file.
5.
Monitor and record the progress of the event until it resolves or reaches a clinically stable 
outcome, with or without sequelae.  For all additional follow-up evaluations, send all 
additional follow-up information on the SAE to the Safety e-mail within 24 hours of 
receipt of the updated information.  SAEs will be monitored until the investigator and 
sponsor agree that the event is satisfactorily resolved.
6.
Obtain and maintain all pertinent medical records and information regarding the SAE in
the subject’s study file.
7.
Inform the sponsor of the final outcome of the event.  Send a follow up SAE form, when
appropriate, to the Safety e-mail.
8.
Prompt notification of SAEs by the investigator to the sponsor is essential so that legal 
obligations and ethical responsibilities towards the safety of subjects are met. 
The sponsor has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a product under clinical investigation. The 
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sponsor will comply with country specific regulatory requirements relating to safety 
reporting to regulatory authorities, institutional review boards (IRBs), and investigators. 
Investigator safety reports are prepared for Suspected Unexpected Serious Adverse 
Reactions (SUSARs) according to local regulatory requirements and the sponsor policy 
and are forwarded to investigators as necessary. An investigator who receives an 
investigator safety report describing a SAE(s) or other specific safety information (e.g., 
summary or listing of SAEs) from the sponsor will file it with the IB and will notify the 
IRB, if appropriate, according to local requirements.
9.
Comply with the applicable regulatory requirement(s) related to the reporting of SAEs to 
the IRB.
7.2.4.2.3
Procedures for Reporting Pregnancies
Any pregnancy occurring during the clinical study, where the fetus could have been exposed 
to the study product, must be monitored until its outcome in order to ensure the complete 
collection of safety data.
Subjects who become pregnant during the screening period are considered screen failures; they 
are recorded as such in the eCRF and no pregnancy form is to be completed.
If a subject becomes pregnant after the screening period, the investigator is to do the following:
1.
The subject does not need to be withdrawn from the clinical study, i.e. she may continue 
to attend the planned study visits, but no invasive procedure should be conducted (e.g. 
no sample taken for lab test).
2.
Complete the Pregnancy Report Part A as fully as possible.  Send the form within 
24 hours of receipt of the information to the Safety e-mail listed above (and in 
Section 7.2.4.2.3).
3.
Monitor and record the progress of the pregnancy until its outcome.  If necessary and 
approved by the subject or their legal health care representative, contact the subject’s 
regular physician (general practitioner or gynecologist) or hospital staff to obtain further 
details and ask for regular follow up information.
4.
At the outcome of the pregnancy, complete the Pregnancy Report Part B. For all the 
additional evaluations, send the follow-up information to the Safety e-mail within 
24 hours of receipt of the information.  If the subject can no longer be reached (lost to 
follow-up), documentation of the non-response/contact with two phone calls and a letter 
(certified with return receipt) is required.
5.
If the pregnancy leads to an abortion (voluntary abortion, spontaneous abortion or 
therapeutic abortion), in utero death or congenital anomaly, follow the procedure for 
declaration of an SAE (see Section 7.2.4.2.2).
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7.3
Other Assessments
7.3.1
Photography
Standardized digital photographs will be taken of the subject’s glabellar region and the full face 
at baseline (prior to treatment) and at each post-treatment visit.
Each investigator (or designee) will take photographs using identical camera equipment, 
conditions, and settings. Detailed instructions for photography will be provided in a separate 
study manual.
7.3.2
Pregnancy Test
For females of childbearing potential, a urine pregnancy test will be performed prior to 
treatment at screening, baseline (prior to treatment) and Month 12/ET. A negative pregnancy 
test is required for study inclusion. The result will be documented.
7.4
Appropriateness of Measurements
The efficacy and safety measurements used in this study are considered standard 
measurements, and are generally recognized as reliable, accurate, and relevant. 
8.
CLINICAL STUDY VISITS DESCRIPTIONS AND PROCEDURES
8.1
Description of Clinical Study Visits
Please refer to the Schedule of Assessments Table 2.
A written, signed ICF (inclusive of Health Insurance Portability and Accountability Act of 
1996 [HIPAA], and photo and video consent) must be obtained prior to performing any clinical 
study-related evaluations and/or procedures. The subject must be provided with a fully 
completed, dated and signed copy.
8.1.1
Screening/Visit 1 (-14 days to Day 0)
The screening and baseline visits may be performed on the same day; however, a maximum of 
14 days is allowed between the screening and baseline visits.
At the screening visit, the investigator or designee will:
1.
Review and explain the nature of the study to the subject, particularly the prohibited 
activities and constraints (e.g., restrictions for other aesthetic treatments and the use of 
topical and systemic medications, see Section 5.4.5).
2.
Obtain the signed and dated ICF (inclusive of HIPAA, and photo and video consent); 
provide a fully completed dated and signed copy to the subject.
3.
Collect information regarding demographics (i.e., date of birth, gender, race, ethnicity, 
height, and weight), Fitzpatrick skin type, relevant medical history and concurrent 
diseases, previous facial treatments/procedures, previous medications and procedures, 
and concomitant medications and procedures (see Table 2).
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All efficacy, safety and baseline characteristics variables will be presented using descriptive 
statistics within each treatment group, and graphs as appropriate. Continuous data will be 
summarized using n (number of observations), mean, standard deviation, median, minimum 
and maximum value, while categorical data will be presented by n and percentages. All data 
will also be listed in subject data listings.
Subject disposition, completion and discontinuation by study visit, protocol deviations, 
demographics and baseline characteristics, medical history, medical and surgical procedures, 
prior and concomitant medications, will be summarized by treatment group.
For analysis of duration of response and time to onset of treatment response, Kaplan-Meier 
methods will be used, including Kaplan-Meier plots and estimates of the median event.
9.1.3.1
Safety Analysis
All treatment related TEAEs by maximum intensity, treatment unrelated TEAEs by maximum 
intensity, treatment emergent SAEs by causality and maximum intensity, and action taken of 
treatment related TEAEs will be summarized by system organ class (SOC) and preferred term 
(PT) including number of subjects with at least one event, percentages, and number of events. 
All related TEAEs will also be summarized by time to onset and duration. In addition, a short 
summary of the analysis of TEAEs will be provided. AEs occurring before treatment will only 
be provided in subject data listings.
Data for vital signs will be summarized by descriptive statistics with the value at each visit as 
well as the change from baseline. The number and percentage of subjects with 
normal/abnormal results in physical examination will be presented by visit and treatment. A 
shift table will be created to present any change from baseline in normal/abnormal results in 
physical examination across the study visits for each treatment group. The results of the urine 
pregnancy tests will be listed.
All AEs will be monitored by the Sponsor to determine if they meet the criteria of remote 
spread of effect of the toxin or hypersensitivity. A list of preferred terms for these types of 
events will be referenced to in the DMP and will be further analyzed to determine if there is a 
plausible possibility that they represent remote spread of toxin or hypersensitivity. In order to 
perform the analysis, variables including alternative etiology (medical history, concomitant 
medication, or diagnosis which could account for the symptoms), location of QM1114-DP
administration, and temporal relationship to QM1114-DP administration will be considered by 
the Sponsor.
9.1.4
Withdrawals and Deviations
All withdrawn subjects will be listed individually, including at least subject number, date and 
reason for withdrawal, and last visit performed.
Subjects with clinical study protocol (CSP) deviations will be listed individually, including 
subject number and observed deviation. They will also be summarized by study center and in 
total (by treatment group and overall). Depending on the seriousness of the deviation, the 
subject might be excluded from the PP population, which shall be documented prior to database 
lock.
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9.1.5
Inferential Statistical Analyses
The primary efficacy endpoint will be a responder rate based on the subject GAIS at Month 1. 
A responder is defined as a subject who responds at least “Improved” on the GAIS at maximum 
frown. The null hypothesis of no relationship between treatment and responder rate will be 
tested against the alternative hypothesis that there is a relationship between treatment and 
responder rate. The responder rates of the QM1114-DP and placebo will be compared using a 
Cochran-Mantel-Haenszel test, stratified by site, at 5% significance level (2-sided) based on 
the ITT population. Missing Month 1 GAIS data will be imputed with ‘No Change’. For 
consistency across strata (site), the Breslow-Day test will be used to assess the homogeneity of 
the odds ratios across all sites. Depending on the number of sites, pooling of sites may be 
needed.
For the primary efficacy endpoint, consistency of the results will be analyzed using Cochran-
Mantel-Haenszel test stratified by gender, baseline ILA, prior use of botulinum toxin, and 
Fitzpatrick skin type, respectively.
All other efficacy and safety endpoints will be analyzed descriptively as appropriate.
9.2
Sample Size Determination
The study is planned to enroll approximately 120 subjects who will be treated with either 50 U 
of QM1114-DP (90 subjects) or placebo (30 subjects).
9.2.1
Historical Data
9.2.2
Assumptions
9.2.3
Sample Size Calculation
9.2.4
Interim Analysis
Not applicable.  An interim analysis is not planned for this study.
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10.
TRAINING / MONITORING / DATA MANAGEMENT / QUALITY 
ASSURANCE
10.1
Personnel Training
Investigators and other responsible persons should be listed together with their function on the 
signature and delegation log. Study staff shall provide a curriculum vitae or equivalent, as 
appropriate.
It is the responsibility of the principal investigator (PI) to ensure that all personnel involved in 
the study are fully informed of all relevant aspects of the study, including detailed knowledge 
of and documented training in all procedures to be followed.
10.2
Clinical Monitoring
The conduct of the clinical study will be closely monitored by representatives of the sponsor 
to verify adherence to the clinical study protocol, International Council for Harmonisation 
Good Clinical Practice (ICH-GCP) guidelines, and applicable standard operating procedures 
(SOPs).  
The investigator will allow the CRO/sponsor’s representatives, to have direct access to all 
clinical study records, eCRFs, corresponding subject medical records, study product(s) 
dispensing records, and any other documents considered source documentation.  Additionally, 
the CRO/sponsor representative is to have access to the study product storage area and clinical 
study facilities.
The investigator also agrees to assist the representative if required.
10.3
Data Management
Data management based on GCP refers to the activities defined to achieve safe routines to enter 
clinical data information into a database, efficiently and avoiding errors. The data management 
routine includes procedures for database set-up and management, data entry and verification, 
data validation, and documentation of the performed activities including information of 
discrepancies in the process. The data management process will be described in detail in the 
data management plan (DMP).
The database, the data entry screens and program will be designed in accordance with the CSP 
and eCRF template. Data validation will be performed by computerized logical checks and 
manual review. Drugs and events will be coded in accordance with World Health Organization 
(WHO) Drug and medical dictionary for regulatory activities (MedDRA) dictionaries as 
specified in the DMP. Safety data (SAE) in the clinical database will be reconciled against the 
data in the safety database.
When all efforts have been made to ensure that the data recorded in the eCRFs and entered in 
the database is as correct and complete as possible, the clinical database will be locked. Study 
data will be transferred to SAS datasets, which thereafter will be write-protected. Statistical 
analyses will be generated in SAS using data from the locked datasets.
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10.4
Quality Assurance/Audit/Inspection
The clinical study is conducted under the sponsorship of the sponsor in compliance with the 
applicable international and local regulatory requirements as well as applicable ICH guidelines 
and in accordance with the Standard Operation Procedures (SOPs) for clinical study conduct 
and monitoring from the sponsor and/or the CRO.
Audits of clinical study centers may be conducted by the sponsor/CRO representatives, and 
inspection may be performed by Regulatory Authority inspectorates or IRBs before, during, or 
after the clinical study.  
The investigator will allow and assist the CRO/sponsor’s representatives, IRBs and any 
regulatory agency to have direct access to all requested clinical study-related records.
For the audits performed by, or on behalf of, the sponsor auditors, audit certificate(s) will be 
provided by Quality Assurance.
10.5
Changes in Clinical Study Conduct/Amendments
10.5.1
Clinical Study Conduct
With the exception of eliminating an immediate hazard to a subject, the investigator should not 
deviate from the clinical study protocol or implement any changes without written approval 
from the sponsor and prior review and documented approval/favorable opinion from the IRB 
of a protocol amendment.
Changes that involve only logistical or administrative changes to the clinical study protocol are 
authorized.  The investigator should document and explain any deviation from the clinical 
study protocol.
10.5.2
Amendments
The sponsor may modify the clinical study protocol at any time for ethical, medical, or 
scientific reasons. Any amendments will be handled according to applicable local regulations.
The sponsor does not have to notify non-substantial amendments to the competent authorities. 
However, non-substantial amendments should be recorded and detailed in subsequent 
submissions e.g., in the subsequent notification of a substantial amendment.
11.
ETHICS AND GENERAL CLINICAL STUDY CONDUCT CONSIDERATIONS
11.1
Institutional Review Board
This clinical study protocol and all applicable amendments will be reviewed and approved by 
the appropriate IRBs.
11.2
Ethical Conduct of the Clinical Study
This clinical study will be conducted in accordance with the protocol, the HELSINKI 
declaration (1964) and subsequent amendments, and the ICH GCP, and in compliance with 
applicable regulatory requirements. 
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11.3
Subject Information and Consent
All subjects who participate in this clinical study are required to be fully informed about the 
clinical study in accordance with GCPs guidelines, federal regulations, HIPAA, and guidelines 
and in accordance with local requirements.  
The ICF (inclusive of HIPPA, and photo and video consent), approved by an IRB will be fully 
explained to the subject.  The subject must agree to photo consent in order to participate in the 
clinical study. 
Prior to enrollment into the clinical study, the subject and the PI or designee must sign and date 
the consent form(s).  The investigator is responsible for maintaining each subject’s consent 
form(s) in the investigator’s site file and providing each subject with a copy of the signed and 
dated consent form(s).
11.4
Protection of Personal Data
The completion of the study involves the gathering and processing of Personal Data as 
specified in the Regulation (European Union (EU)) 2016/679 on the protection of individuals 
with regard to the processing of personal data and on the free movement of such data. For the 
purposes of the study, sponsor will be considered the Data Controller, and PI and institution 
will both be considered Data Processors.
All processing of Personal Data must be carried out in accordance with national legislation 
concerning the protection of Personal Data. The institution and PI are responsible for 
complying with all requirements pursuant to national legislation in the country in which the 
institution and PI are located.
The PI understands that clinical studies conducted under an Investigational New Drug (IND) 
application are exempt from the study subject identifier confidentiality provisions of HIPAA, 
as provided at Code of Federal Regulations (CFR) § 512(b)(iii), and the study subject should 
be made aware of this exception in the informed consent. The sponsor shall, to the extent 
feasible, protect study subject identifier information.
The institution and PI are jointly responsible for obtaining the appropriate informed consent of 
each subject for the processing of Personal Data required in order to complete the study. Such 
consent shall include the consent to the transfer of Personal Data to government authorities 
located in countries outside the US. 
The institution and PI are jointly responsible for providing sufficient information to all subjects 
to enable them to give their informed consent not only to the participation in the study, but also 
to the processing of Personal Data. Such information includes information regarding the 
purposes of the processing, the length of time during which Personal Data will be stored, the 
right of access to stored Personal Data and the right to correction or purging of incorrect or 
obsolete Personal Data. A subject may also withdraw his or her consent at any time during or 
after the study. A subject who withdraws his or her consent to the processing of Personal Data 
must be considered to have withdrawn from the study but the data collected until the consent 
was withdrawn may be used in the statistical analyses or to comply with legal or administrative 
requirements.
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All collection, processing and analyses of protected health information, personal data or similar 
will be conducted in compliance with applicable local, national and international rules, 
regulations and guidelines.
11.5
Contractual Requirements
A contractual agreement will be signed between the CRO/sponsor and each investigator/
institution.  This document will contain supplementary information, including financial terms, 
confidentiality, the clinical study schedule, third party responsibility, and publication rights.
11.6
Data Collection and Archiving
11.6.1
Data Collection
The investigator must maintain all required records for all subjects.  Data for this clinical study
will be recorded in the subject’s source documents and in the eCRFs provided by the sponsor.  
All data should be recorded in the eCRFs completely and promptly.
11.6.2
Source Documentation
The investigator must keep accurate separate records (other than the eCRFs) of all subject 
visits, being sure to include all pertinent clinical study-related information.  A statement should 
be made indicating that the subjects have been included in this clinical study and have provided 
signed written Informed Consent.  All AEs must be thoroughly documented.
Results of any diagnostic tests conducted during the clinical study should also be included in 
the source documentation.  
11.6.3
Archives
All pertinent data, samples, photographs, correspondence, and reports, the original or amended 
clinical study protocol, and all other material relating to the clinical study will be maintained 
securely in sponsor/CRO/investigator/institution archives for the legally required duration for 
archiving.
The investigator/institution should maintain the essential clinical study documents as specified 
in Section 8 of ICH-GCP, and according to the applicable regulatory requirements.
The investigator/institution should take measures to prevent accidental or premature 
destruction of these documents.
If the PI retires, relocates, or withdraws from the responsibility of keeping the clinical study
records for any other reasons, custody must be transferred to a person who will accept the 
responsibility.  The sponsor/CRO must be notified in writing of the name and address of the 
new custodian.
11.7
Insurance
A certificate attesting Third Party coverage of CRO/sponsor will be provided upon request.
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11.8
Publication Policy
The institution/PI’s and the sponsor’s obligations regarding intellectual property rights, 
confidentiality, and publications are described in detail in the clinical trial agreement (CTA).
The aim is to submit the results of this study for publication in a public database (e.g., 
www.ClinicalTrials.gov) and to a medical journal for publication of the results. Everyone who 
is to be listed as an author of the results of this multicenter study shall have made a substantial, 
direct, intellectual contribution to the work. Authorship will be based on (1) substantial 
contributions to the conception or design of the work; or the acquisition, analysis, or 
interpretation of data for the work; and (2) drafting the work or revising it critically for 
important intellectual content; and (3) final approval of the version to be published; and (4) 
agreement to be accountable for all aspects of the work in ensuring that questions related to the 
accuracy or integrity of any part of the work are appropriately investigated and resolved.a
Conditions 1, 2, 3, and 4 must all be met in order to be designated as author. Those who do not 
meet all four criteria will be acknowledged. Among the authors that fulfil the above mentioned 
criteria, one author will be appointed by the sponsor to take primary responsibility for the 
overall work as primary author.
                                                
a Defining the role of authors and contributors, compiled by the International Committee of Medical Journal 
Editors (ICMJE) (http://www.icmje.org).
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11.9
Investigator and Administrative Structure 
Role
Contact Information
Sponsor Contact:
Galderma Research and Development, LLC
14501 North Freeway
Fort Worth, TX 76177
Phone: 
E-mail: 
Medical Monitor:
Phone: 
E-mail: 
Safety e-mail for SAE, Pregnancy 
Reporting, and PQC:
E-mail:
CRO:
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12.
LITERATURE REFERENCE LIST
1.
ICH E6: International Conference on Harmonisation Tripartite Guideline:  Guideline for Good 
Clinical Practice. 1996 
2.
Sundaram, H., M. Signorini, S. Liew, A. R. Trindade de Almeida, Y. Wu, A. Vieira Braz, S. Fagien, 
G. J. Goodman, G. Monheit, H. Raspaldo and G. Global Aesthetics Consensus (2016). "Global 
Aesthetics Consensus: Botulinum Toxin Type A--Evidence-Based Review, Emerging Concepts, 
and Consensus Recommendations for Aesthetic Use, Including Updates on Complications." Plast 
Reconstr Surg 137(3): 518e-529e.
3.
Awan, K. H. (2017). "The therapeutic usage of botulinum toxin (Botox) in non-cosmetic head and 
neck conditions - An evidence based review." Saudi Pharm J 25(1): 18-24.
4.
Scott AB. Botulinum toxin injection into extraocular muscles as an alternative to strabismus
surgery. Ophthalmology.  1980;87:1044-9.
5.
Monheit, G. D. and A. Pickett (2017). "AbobotulinumtoxinA: A 25-Year History." Aesthet Surg J 
37(suppl_1): S4-s11.
6.
Dressler, D., S. Vogt and F. Saberi (2016). "Der Off-Label Use am Beispiel der Botulinumtoxin-
Therapie." Klinische Neurophysiologie 47(02): 87-91.
7.
Lupo, M. P. (2016). "Tox Outside the Box: Off-Label Aesthetic Uses of Botulinum Toxin." J Drugs 
Dermatol 15(9): 1151-1157.
8.
Campanati, A., E. Martina, K. Giuliodori, V. Consales, I. Bobyr and A. Offidani (2017). 
"Botulinum Toxin Off-Label Use in Dermatology: A Review." Skin Appendage Disord 3(1): 39-56.
9.
Carruthers, J. and A. Carruthers (2007). "The evolution of botulinum neurotoxin type A for 
cosmetic applications." J Cosmet Laser Ther 9(3): 186-192
10. Rzany, B., D. Dill-Muller, D. Grablowitz, M. Heckmann, D. Caird and G. German-Austrian 
Retrospective Study (2007). "Repeated botulinum toxin A injections for the treatment of lines in 
the upper face: a retrospective study of 4,103 treatments in 945 patients." Dermatol Surg 33(1 Spec 
No.): S18-25.
11. Pirazzini, M., O. Rossetto, R. Eleopra and C. Montecucco (2017). "Botulinum Neurotoxins: 
Biology, Pharmacology, and Toxicology." Pharmacol Rev 69(2): 200-235.
12. Investigator’s Brochure QM1114-DP (Botulinum Neurotoxin Type A) Upper Facial Wrinkles, 
Version 6, 2021-07-02.
13. Pusic AL, Klassen AF, Scott AM, Cano SJ. Development and psychometric evaluation of the 
FACE-Q satisfaction with appearance scale: a newpatient-reported outcome intrsument for facial 
aesthetic patients. Clin Plast Surg 2013;40(2):249-260
14. Klassen AF, Cano SJ, Scott AM, Pusic AL. Measuring outcomes that matter to face-lift patients: 
development and validation of FACE-Q appearance appraisal scales and adverse affects checklist 
for the lower face and neck. Plast Reconstr Surg 2014;133(1):21-30
15. ICH E2A: International Conference on Harmonisation Tripartite Guideline:  Clinical Safety 
Data Management: Definitions and Standards for Expedited Reporting. 1994
16. FDA Guidance for Industry. Upper Facial Lines: developing botulinum toxin drug products 
(draft), 2014.
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14.
APPENDICES
Appendix 7:
Focused Physical Examination Form Example
Appendix 8:
Adverse Events Potentially Suggestive of Remote Spread of Toxin 
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Appendix 7
Focused Physical Examination Form Example
Not done  
     Provide details: ___________________________________________________
General Health Assessment: Complete at Screening, Baseline (prior to treatment), and all post-treatment 
visits.
Question the subject about their general health (general wellbeing/ bodily functions, e.g., arms, legs, stomach/ 
bladder/ bowel, also refer to the list of Adverse Events Potentially Suggestive of Distant Spread of Toxin
(Appendix 8). Clinically significant abnormalities noted pre-injection should be recorded as medical history and 
Investigator should confirm if any abnormalities affect subject eligibility. Clinically significant abnormalities 
noted post-injection should be documented as AEs.
Next, proceed to the Focused Physical Examination (Part 1 and 2) as indicated below.
Part 1: Complete at Screening, Baseline (prior to treatment), and all post-treatment visits.
Please perform a targeted examination of the face, head, and neck recording abnormalities and assess clinical 
significance.
Part 1 Examination
Normal
Abnormal (provide details)
Eyelid position
Clinically Significant
Not Clinically Significant
Eyebrow position
Clinically Significant
Not Clinically Significant
Vision abnormalities (not 
refractive errors)
Clinically Significant
Not Clinically Significant
Throat function (e.g., 
swallowing/drink water)
Clinically Significant
Not Clinically Significant
Ability to talk and chew
Clinically Significant
Not Clinically Significant
Ability to stick out and move 
tongue
Clinically Significant
Not Clinically Significant
Ability to lift shoulders 
Clinically Significant
Not Clinically Significant
Investigator Signature
Date
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PART 2: Complete at all post-treatment visits.
Not done  
     Provide details: _____________________________________________________
After questioning the subject about their general health and performing Part 1, determine if there are any 
clinically significant abnormalities that may suggest local or remote spread of toxin effect.
-
Local Spread of Toxin Effect refers to effects in areas adjacent to the treatment area (e.g., lower 
frontalis, periorbital area, medial part of temporalis).
-
Remote Spread of Toxin Effect refers to effects in other body parts, not adjacent to the treatment area, 
when effect can only be attributed to the toxin and there is no other medically sound cause.
-
Determine if the event is clinically significant (i.e., would affect subject safety, confound the study 
data, or requires medical treatment) and document on the source document.
Please refer to the list of remote spread of toxin events (Appendix 8) while doing clinical evaluations based on 
subject’s symptoms and signs. Directed questioning and examination will then be performed as appropriate. If 
yes, please describe.
Part 2 Examination
No
Yes* (provide details)
Targeted Physical Examination of Face 
and Neck to Evaluate Local Spread of 
Toxin Effect
Local spread of toxin effect event(s) 
observed?

General Physical Examination to 
Evaluate the Remote Spread of Toxin 
Effect
Remote spread of toxin effect event(s) 
observed?

* Clinically significant abnormalities should be documented as AE.
Additional comments for Focused Physical Exam: 
__________________________________________________________________________________________
__________________________________________________________________________________________
__________________________________________________________________________________________
Investigator Signature
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Appendix 8
Adverse Events Potentially Suggestive of Remote Spread of Toxin
The following adverse events may potentially be suggestive of remote spread of toxin (based on 
FDA Guidance for Industry: Upper Facial Lines: Developing Botulinum Toxin Drug Products; 
August 2014).16
accommodation disorder
eyelid function disorder
paresis cranial nerve
areflexia
eyelid ptosis
peripheral nerve palsy
aspiration
facial palsy
peripheral paralysis
blurred vision
facial paresis
pelvic floor muscle weakness
botulism
fourth cranial nerve paresis
pneumonia aspiration
Bradycardia
hemiparesis
pupillary reflex impaired
bulbar palsy
hypoglossal nerve paresis
quadriparesis
constipation
hyporeflexia
respiratory arrest
cranial nerve palsies
hypotonia
respiratory depression
cranial nerve paralysis
monoparesis
respiratory distress
diaphragmatic paralysis
muscular weakness
respiratory failure
diplopia
neuromuscular toxicity
respiratory paralysis
dry mouth
paralysis
speech disorder
dysarthria
paralysis flaccid
third cranial nerve paresis
dysphagia
paralysis recurrent laryngeal nerve
trigeminal nerve paresis
dysphonia
paralytic ileus
urinary retention
dyspnea
paraparesis
vocal cord paralysis
extraocular muscle paresis
paresis
vocal cord paresis
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SIGNED AGREEMENT OF THE CLINICAL STUDY PROTOCOL (CSP)
Clinical Trial Number (CTN):
43QM2106
CSP title:
A Phase 3b, Randomized, Double-Blind, Placebo-
Controlled Study to Assess Aesthetic Improvement and 
Onset of QM1114-DP Treatment Effect in Subjects with 
Moderate to Severe Glabellar Lines 
I, the undersigned, have read and understand the CSP specified above, and agree on the 
contents. The CSP, the clinical trial agreement (CTA) and the additional information given in 
the Investigator’s Brochure (IB) will serve as a basis for co-operation in this study.
Principal Investigator
Printed name 
Signature
Date
Study center
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Sign page:1 of 1
SIGNATURES PAGE
Date
Signed by
2022-03-18 08:10
Justification
Compiled by
2022-03-18 09:28
Justification
Approved by Technical Expert
2022-03-20 07:40
Justification
Approved by Technical Expert
2022-03-21 10:51
Justification
Approved by Technical Expert
2022-03-21 13:08
Justification
Approved by Owner
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