A Multicenter, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy and Safety of QM1114-DP for the Treatment of Moderate to Severe Glabellar Lines
Phase: PHASE3
Conditions: Glabellar Frown Lines
Sponsor: Galderma R&D

CONFIDENTIAL 
Page 1 of 84
CLINICAL STUDY PROTOCOL
PROTOCOL NUMBER: 43QM1602
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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TITLE PAGE
A Multicenter, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy and 
Safety of QM1114-DP for the Treatment of Moderate to Severe Glabellar Lines
(READY - 1)
Clinical Trial Number (CTN): 43QM1602
IND Number:
SPONSOR:
Name:
Q-Med AB, a Galderma affiliate
Address:
Seminariegatan 21
SE-752 28 Uppsala, Sweden
Phone:
+46 18 474 90 00
CONTRACT RESEARCH ORGANIZATION (CRO):
Name:
Address:
Phone:
SAFETY:
For safety questions, please contact the Safety e-mail or Medical Monitor using the details provided 
in Section 0. Serious adverse events (SAEs) and pregnancy report forms should be submitted as 
described in Sections 7.2.6.2.2 and 7.2.6.2.3.
MEDICAL MONITOR:
For any medical questions related to the clinical study protocol, please contact the Medical Monitor
using the details provided in Section 0.
This clinical study shall be performed in compliance with the clinical trial agreement (CTA), the 
clinical study protocol (CSP), ICH-Good Clinical Practice (GCP),1 and applicable regional and 
national regulations. The study shall be conducted in accordance with the ethical principles that have 
their origin in the Declaration of Helsinki (https://www.wma.net/policies-post/wma-declaration-of-
helsinki-ethical-principles-for-medical-research-involving-human-subjects/).
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Table of Contents
TITLE PAGE..................................................................................................................................................2
SYNOPSIS ......................................................................................................................................................9
CLINICAL STUDY SCHEMATIC AND FLOW CHART......................................................................15
SCHEDULE OF ASSESSMENTS..............................................................................................................17
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ...........................................................18
1.
BACKGROUND AND RATIONALE ........................................................................................22
1.1
Medical Background and Short Rationale for the Clinical Study............................................22
1.2
Study Product Profile ...................................................................................................................23
1.2.1
Drug Profile..............................................................................................................................23
1.2.2
Pre-Clinical Documentation....................................................................................................23
1.2.3
Clinical Documentation...........................................................................................................24
1.2.4
Dose Rationale..........................................................................................................................25
1.3
Risk/Benefit Assessment...............................................................................................................25
2.
CLINICAL STUDY OBJECTIVES, ENDPOINTS, AND CLINICAL 
HYPOTHESIS...............................................................................................................................26
2.1
Clinical Study Objectives .............................................................................................................26
2.1.1
Primary Efficacy Objectives and Endpoints .........................................................................26
2.1.2
Secondary Efficacy Objective and Endpoints .......................................................................27
2.1.4
Safety Objectives and Endpoints............................................................................................28
2.2
Clinical Hypothesis .......................................................................................................................29
3.
OVERALL CLINICAL STUDY DESCRIPTION.....................................................................29
4.
CLINICAL STUDY DURATION AND TERMINATION .......................................................30
5.
SELECTION AND DISPOSITION OF CLINICAL STUDY POPULATION.......................30
5.1
Number of Subjects.......................................................................................................................30
5.2
Clinical Study Population Characteristics..................................................................................30
5.2.1
Inclusion Criteria.....................................................................................................................30
5.2.2
Exclusion Criteria....................................................................................................................31
5.3
Medical History.............................................................................................................................33
5.4
Previous and Concomitant Therapies.........................................................................................33
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5.4.1
Definition ..................................................................................................................................33
5.4.2
Categories .................................................................................................................................33
5.4.3
Recording..................................................................................................................................34
5.4.4
Authorized Concomitant Therapies.......................................................................................34
5.4.5
Prohibited Concomitant Therapies........................................................................................34
5.5
Procedures/Reasons for Subject Discontinuation ......................................................................35
6.
CLINICAL SUPPLIES ................................................................................................................36
6.1
Clinical Supply Identification and Use........................................................................................36
6.1.1
QM1114-DP..............................................................................................................................36
6.1.2
Placebo......................................................................................................................................36
6.1.3
Study Products(s) Description ................................................................................................37
6.1.4
Subject Identification Number (SIN).....................................................................................37
6.1.5
Method of Treatment Assignment..........................................................................................37
6.1.6
Kit Number/Randomization Number ....................................................................................38
6.1.7
Instructions for Use and Administration...............................................................................38
6.1.7.1
Treatment Procedure .........................................................................................................38
6.1.7.2
Post-treatment Care ...........................................................................................................39
6.1.7.3
Treatment Regimen............................................................................................................39
6.2
Study Products(s) Packaging and Labeling................................................................................39
6.3
Supplies Management...................................................................................................................40
6.3.1
Accountability ..........................................................................................................................40
6.3.2
Storage of Study Product(s) ....................................................................................................40
6.3.3
Dispensing and Return ............................................................................................................40
6.3.4
Treatment Compliance Management and Record................................................................40
6.3.5
Dose Modification ....................................................................................................................40
6.3.6
Product Quality Complaints...................................................................................................40
6.4
Blinding..........................................................................................................................................41
6.4.1
Verification of Blinding...........................................................................................................41
6.4.2
Unblinding During the Clinical Study ...................................................................................41
7.
CLINICAL STUDY ASSESSMENT...........................................................................................42
7.1
Efficacy Assessments.....................................................................................................................42
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7.1.1
4-point Photographic Scale of Glabellar Line Severity: Investigator Live 
Assessment (GL-ILA)..............................................................................................................42
7.1.2
Static 4-point Categorical Scale of Glabellar Line Severity: Subject Live 
Assessment (GL-SLA) .............................................................................................................42
7.2
Safety Assessments........................................................................................................................44
7.2.1
Focused Physical Examination (FPE) ....................................................................................44
7.2.2
Vital Signs.................................................................................................................................45
7.2.3
Electrocardiogram (ECG).......................................................................................................45
7.2.4
Laboratory Safety Tests ..........................................................................................................45
7.2.5
Neutralizing Antibody Testing................................................................................................46
7.2.6
Adverse Events.........................................................................................................................46
7.2.6.1
Definitions............................................................................................................................47
7.2.6.1.1
Adverse Events (AE) ........................................................................................................47
7.2.6.1.2
Treatment Emergent Adverse Event (TEAE)...................................................................47
7.2.6.1.3
Serious Adverse Events (SAE) .........................................................................................48
7.2.6.1.4
Unexpected Adverse Drug Reaction................................................................................48
7.2.6.1.5
Adverse Event Reporting Period .....................................................................................48
7.2.6.1.6
Severity ............................................................................................................................49
7.2.6.1.7
Relationship to the Study Product and/or Clinical Study Procedure..............................49
7.2.6.2
Reporting Procedures.........................................................................................................50
7.2.6.2.1
Procedures for Reporting Adverse Events.......................................................................50
7.2.6.2.2
Procedure for Reporting a Serious Adverse Event..........................................................50
7.2.6.2.3
Procedures for Reporting Pregnancies ...........................................................................51
7.3
Other Assessments ........................................................................................................................52
7.3.1
Photography .............................................................................................................................52
7.3.2
Pregnancy Test.........................................................................................................................52
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7.4
Appropriateness of Measurements..............................................................................................53
8.
CLINICAL STUDY VISITS DESCRIPTIONS AND PROCEDURES...................................53
8.1
Description of Clinical Study Visits.............................................................................................53
8.1.1
Screening/Visit 1 (-14 days to Day 0)......................................................................................53
8.1.2
Baseline/Visit 2 [Day 0]............................................................................................................54
8.1.3
Day 7/Visit 3 (±1 day) ..............................................................................................................55
8.1.4
Day 14/Visit 4 (±3 days)...........................................................................................................56
8.1.5
Month 1/Visit 5 (±5 days) ........................................................................................................57
8.1.6
Months 2-5/Visit 6-9 (±5 days)................................................................................................58
8.1.7
Month 6/Visit 10 or Early Termination visit (±5 days) ........................................................58
8.2
Unscheduled Visits........................................................................................................................59
8.3
Subject Instructions......................................................................................................................59
9.
STATISTICAL METHODS PLANNED....................................................................................59
9.1
Statistical and Analytical Plans ...................................................................................................59
9.1.1
Data Transformations .............................................................................................................60
9.1.2
Populations Analyzed and Evaluability.................................................................................60
9.1.2.1
Modified Intent-to-treat (mITT) Efficacy Population.....................................................60
9.1.2.2
Intent-to-treat (ITT) Efficacy Population.........................................................................60
9.1.2.3
Per-protocol (PP) Efficacy Population..............................................................................60
9.1.2.4
Safety Population................................................................................................................61
9.1.2.5
Imputation of Missing Data ...............................................................................................61
9.1.3
Data Presentation and Graphics.............................................................................................61
9.1.3.1
Subgroup Analysis..............................................................................................................61
9.1.3.2
Safety Analysis ....................................................................................................................62
9.1.4
Withdrawals and Deviations...................................................................................................62
9.1.5
Inferential Statistical Analyses ...............................................................................................62
9.2
Sample Size Determination ..........................................................................................................63
9.2.3
Sample Size Calculation ..........................................................................................................64
9.2.4
Interim Analysis.......................................................................................................................64
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10.
TRAINING / MONITORING / DATA MANAGEMENT / QUALITY 
ASSURANCE ................................................................................................................................64
10.1
Personnel Training........................................................................................................................64
10.2
Clinical Monitoring.......................................................................................................................65
10.3
Data Management.........................................................................................................................65
10.4
Quality Assurance/Audit/Inspection ...........................................................................................65
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
Independent Ethics Committee (IEC) or Institutional Review Board (IRB) ..........................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 .......................................................................................................................................69
11.8
Publication Policy..........................................................................................................................69
11.9
Investigator and Administrative Structure ................................................................................70
12.
Summary of Changes in Clinical Study Protocol 43QM1602 ........................................................71
12.1
Protocol Version 3.0 to Version 4.0 .............................................................................................71
13.
LITERATURE REFERENCE LIST................................................................................................73
14.
APPENDICES ....................................................................................................................................74
Appendix 1
Validated Investigator 4-point Photographic Scale of Glabellar Line Severity 
(GL-ILA)........................................................................................................................................74
Appendix 5
Focused Physical Examination Form Example................................................................81
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Appendix 6
Adverse Events Potentially Suggestive of Remote Spread of Toxin...............................83
SIGNED AGREEMENT OF THE CLINICAL STUDY PROTOCOL ..................................................84
List of Tables
Table 1
Clinical Study Schematic........................................................................................................ 15
Table 2
Schedule of Assessments........................................................................................................ 17
Table 3
Description and Usage of the Study Products(s) .................................................................... 37
List of Figures
Figure 1 
Study Flow Chart.................................................................................................................... 16
Figure 2
Injection Sites for Treating Glabellar Lines............................................................................ 39
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SYNOPSIS
Clinical Study Title: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy 
and Safety of QM1114-DP for the Treatment of Moderate to Severe Glabellar Lines (READY - 1)
Short Title: QM1114-DP Glabellar Lines
Clinical Study Population:
Male and female subjects, 18 years of age and older, with moderate to severe 
glabellar lines (GL) at maximum frown.
Clinical Study Design:
This is a phase 3, multi-center, randomized, double blind, placebo-controlled study to 
evaluate the efficacy and safety of 50 units (U) of QM1114-DP for the treatment of 
moderate to severe GL. 
Following the informed consent and the screening process, eligible subjects will be 
randomly assigned in a 3:1 ratio to receive a single treatment at baseline of 50 U
QM1114-DP (225 subjects) or placebo (75 subjects) in the GL area. Randomization 
will be stratified by study center. 
Each subject will receive a single treatment divided equally among 5 injection points 
(0.1 mL per injection point) in the glabellar region.
Following treatment at baseline, subjects will be monitored for safety and efficacy for 
6 months.
Target Indication:
This study is designed to evaluate the safety and efficacy of QM1114-DP for the 
treatment of moderate to severe GL.
Total Number of Subjects 
(Planned): 
Approximately 300 subjects will be enrolled.
Number of Clinical Study
Centers (Planned):
Up to 15 centers
Region(s) / Country(ies) 
Involved (Planned):
US and Canada
Clinical Study Duration:
The planned duration of recruitment (from first subject first visit [FSFV] to last subject 
first visit [LSFV]) is approximately 3 months.
The planned clinical study duration (from FSFV to last subject last visit [LSLV]) is 
approximately 9.5 months.
Duration of Subject 
Participation: 
Clinical study participation for each subject is up to 6.5 months.
Key Inclusion Criteria:
1.
Male or female 18 years of age or older.
2.
Moderate to severe GL (grade of 2 or 3 on the 4-point Photographic Scale
ranging from 0 [none] to 3 [severe]) at maximum frown as assessed by the 
Investigator (GL-ILA).
3.
Moderate to severe GL (grade of 2 or 3 on the Static 4-Point Categorical Scale
ranging from 0 [no wrinkles] to 3 [severe wrinkles]) at maximum frown as 
assessed by the subject (GL-SLA).
4.
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;
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SYNOPSIS
Clinical Study Title: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy 
and Safety of QM1114-DP for the Treatment of Moderate to Severe Glabellar Lines (READY - 1)

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;

Intra uterine 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 duration 
of the subject’s participation in the study).
5.
Time and ability to complete the study and comply with instructions.
6.
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 glabellar lines 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 micro blading 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 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 
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SYNOPSIS
Clinical Study Title: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy 
and Safety of QM1114-DP for the Treatment of Moderate to Severe Glabellar Lines (READY - 1)
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, buffered solution for injection
Strength/Concentration:
100 U/mL
Dosage (total daily dose):
50 U total (0.5 mL total)
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
Placebo Product:
Placebo, buffered solution for injection
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
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SYNOPSIS
Clinical Study Title: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy 
and Safety of QM1114-DP for the Treatment of Moderate to Severe Glabellar Lines (READY - 1)
Efficacy Assessment:

4-point Photographic Scale of GL Severity at 
maximum frown (Investigator 
assessment [GL-ILA])

Static 4-point Categorical Scale of GL Severity at maximum frown (subject 
assessment [GL-SLA])
Study Objective:
The objective of the study is to evaluate the efficacy and safety of a single dose of 50 
U of QM1114-DP compared to placebo for the treatment of moderate to severe GL.
Primary Efficacy Objective 
and Endpoint:
The primary efficacy objective is to evaluate a single dose of 50 U of QM1114-DP 
compared to placebo for the treatment of moderate to severe GL.
For the primary endpoint, the composite responder rate will be evaluated at Month 1 
using the GL-ILA and the GL-SLA at maximum frown. 
A composite responder is defined as a subject who achieves a score of 0 or 1 in GL 
severity and at least 2 grades improvement from baseline on both the GL-ILA and GL-
SLA scales concurrently.
Secondary Efficacy 
Objective and Endpoints:
The secondary objective is to evaluate the efficacy of a single dose of 50 U of 
QM1114-DP compared to placebo for the treatment of moderate to severe GL.
Endpoints:
Percentage of subjects who achieve a score of 0 or 1 at:

Month 1 using the GL-ILA at maximum frown

Each post-treatment visit (excluding Month 1) using the GL-ILA at maximum 
frown
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SYNOPSIS
Clinical Study Title: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy 
and Safety of QM1114-DP for the Treatment of Moderate to Severe Glabellar Lines (READY - 1)
Safety Assessment:

Adverse events (AEs)

Focused physical examination (FPE)

Vital signs

Electrocardiogram (ECG)

Laboratory safety tests (chemistry and hematology)

Production of neutralizing antibodies against QM1114-DP
Safety Objectives and 
Endpoints:
To evaluate the safety of a single dose of 50 U of QM1114-DP compared to placebo 
for the treatment of moderate to severe GL.
Endpoints:

Incidence and severity of treatment emergent AEs (TEAEs)

FPE findings

Vital signs

ECG

Laboratory parameters (clinical chemistry and hematology)

Neutralizing antibody production
Other Assessments: 

Photography

Pregnancy test
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SYNOPSIS
Clinical Study Title: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy 
and Safety of QM1114-DP for the Treatment of Moderate to Severe Glabellar Lines (READY - 1)
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.
Principal Statistical 
Method:
The primary efficacy endpoint will be a composite responder rate based on the ILA 
and SLA of GL severity at maximum frown at Month 1. A responder is defined as a 
subject who achieves a score of 0 or 1 and at least 2 grades improvement from 
baseline on both scales concurrently. The responder rates of QM1114-DP and 
placebo will be compared using Cochran-Mantel-Haenszel test (stratified by center) 
at 5% significance level (2-sided). 
Secondary endpoints will be analyzed using the Cochran-Mantel-Haenszel test 
(stratified by center). The fixed sequence testing procedure will be used to control the 
type I error rate for the multiple testing.
safety endpoints, will be analyzed
descriptively as appropriate. P-values might be provided for descriptive purposes. 
Percentages of subjects over time will be presented in graphs. Duration of effect and 
time to onset will be analyzed with Kaplan-Meier methods.
Sample Size:
The study is planned to enroll approximately 300 subjects who will be treated with 
either 50 U of QM1114-DP (225 subjects) or placebo (75 subjects). The sample size 
is determined by the number of subjects exposed to QM1114-DP in the GL.
Interim Analysis (IA):
Not applicable.  An interim analysis is not planned for this study. 
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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=225
n=75
Treatment 
QM1114-DP 50 units
Placebo
Treatment Frequency
Single treatment at baseline
Single treatment at baseline
                                     
                                     Follow up Visits
                                    Days 7 and 14, Months 1, 2, 3, 4, 5, and 6/ET
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Figure 1
Study Flow Chart
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SCHEDULE OF ASSESSMENTS
Table 2
Schedule of Assessments
1 month = 4 weeks/28 days
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
Visit 10
Screening1
Baseline/Day 01
(within 2 weeks after 
screening)
Day 7
(±1 day)
Day 14
(3 days)
Month 1
(5 days)
Month 2
(5 days)
Month 3
(5 days)
Month 4
(5 days)
Month 5
(5 days)
Month 6/ET2
(5 days)
Informed Consent
X
Demographic Data3 including, Fitzpatrick skin type, medical 
history & concurrent diseases, previous facial 
treatments/procedures (toxin naïve/non-toxin naïve)
X
Inclusion /Exclusion Criteria
X
X4
Concomitant Therapies/ Procedures 
X
X5
X
X
X
X
X
X
X
X
Adverse Events
X
X5
X
X
X
X
X
X
X
X
Urine Pregnancy Test6
X
X4
X
Vital Signs (blood pressure, heart rate, and respiratory rate)7
X5
X
X
X
X
ECG
X4
X
X
Blood sample clinical chemistry and hematology
X4
X
Blood sample for serum antibody testing
X4
X
X
ILA of GL Severity 
X
X4
X
X
X
X
X
X
X
X
Focused Physical Examination (face, head, neck)8
X
X4
X
X
X
X
Photography
X4
X
X
X
X
X
X
X
X
Randomization
X4
Treatment
X9
Subject Assessments
SLA of GL Severity10
X
X4
X
X
X
X
X
X
X
X
1.
Screening and baseline visits may be on the same day. If completed on the same day, only perform study 
assessments once (i.e., PE, UPT, SLA, ILA, AE, concomitant therapies/procedures, inclusion/exclusion review).
2.
If the subject withdraws before the final visit the assessments at Month 6/ET should be completed, if possible.
3.
Includes date of birth, gender, race, ethnicity, height, weight.
4.
To be performed before treatment.
5.
Performed before treatment and post-treatment.
6.
Females of childbearing potential
7.
Vital signs are taken seated after 10 minutes rest. Vital signs are taken prior to any blood draw (excluding post-
treatment measurements on Day 0).
8.
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.
9.
Following treatment administration, subjects will be monitored at the study center for 30 minutes. 
10.
Subjects will make their GL assessments independently of the Investigator’s assessment.
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation/Term
Definition
C
Degrees Celsius
AE 
Adverse Event
ALP
Alkaline Phosphatase
ALT/ALAT (SGPT)
Alanine Aminotransferase (Serum Glutamic Pyruvic Transaminase)
AST/ASAT (SGOT)
Aspartate 
Aminotransferase 
(Serum 
Glutamic 
Oxaloacetic 
Transaminase)
BoNT
Botulinum Toxin
BoNT-A
Botulinum Toxin Type A
CFR
Code of Federal Regulations
CRO
Contract Research Organization
CSP
Clinical Study Protocol
CSR
Clinical Study Report
CTA
Clinical Trial Agreement
CTN
Clinical Trial Number
DMP
Data Management Plan
ECG
Electrocardiogram
eCRF
Electronic Case Report Form
EDC
Electronic Data Capture
e.g. 
For Example (Latin: exempli gratia)
ET
Early Termination
F
Degrees Fahrenheit
FDA
Food and Drug Administration
FSFV
First Subject First Visit (first subject screened, i.e. who signs the 
informed consent form)
FSLV
First Subject Last Visit
GCP 
Good Clinical Practice 
GGT
Gamma Glutamyl Transferase
GL
Glabellar Lines
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Abbreviation/Term
Definition
GLP
Good Laboratory Practices
Hb
Haemoglobin
Hct
Hematocrit
HIPAA
Health Insurance Portability and Accountability Act of 1996
IB
Investigators Brochure
ICF
Informed Consent Form
ICH
International Council for Harmonisation 
i.e. 
That is (Latin: id est)
ILA
Investigator Live Assessment
IM
Intramuscular
IND
Investigational New Drug
Investigator
The Principal Investigator (PI) or other qualified person, i.e. sub-
Investigator, designated and supervised by the PI at a study site to 
perform critical study-related procedures or to make important study-
related decisions as specified on the signature and delegation log
Investigator File
Essential documents relating to a clinical study as defined in 
applicable GCP guidance document and maintained by the 
Investigator.
Investigational Product
A pharmaceutical form of an active ingredient being tested in a clinical 
study, including a product with a marketing authorization when used 
or assembled (formulated or packaged) in a way different from the 
approved form, or when used for an unapproved indication, or when 
used to gain further information about an approved use.
IRB
Institutional Review Board
ITT
Intention-to-treat
IUD
Intrauterine Device
kDa
Kilodalton
LSFV
Last Subject First Visit (last subject screened, i.e. who signs the
informed consent form)
LSLV
Last Subject Last Visit (last subject who completed its last clinical 
study visit)
MAS
Merz Aesthetics ScaleTM
MD
Medical Doctor
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Abbreviation/Term
Definition
MedDRA
Medical Dictionary for Regulatory Activities
mITT
Modified Intention-to-treat
Mg
Milligram
mL
Milliliter
MTD
Maximum tolerated dose
N or n
Number
N/A
Not Applicable
OTC
Over-the-Counter
PE
Physical Examination
PI
Principal Investigator; qualified person responsible for conducting the 
study at a study site
Plt
Platelet count
PP
Per-Protocol
PQC
Product Quality Complaint
PT
Preferred Term
QA
Quality Assurance
RA
Regulatory Authority
RBC
Red blood cell
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
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
TEAE
Treatment Emergent Adverse Event
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Abbreviation/Term
Definition
UPT
Urine Pregnancy Test
US
United States
v/v
Volume/volume
WBC
White blood cell
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 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, 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
Study Product Profile
1.2.1
Drug Profile
QM1114 is a protein dimer of 150 kilodalton (kDa) 
 Unlike other commercially 
available BoNTs, QM1114-DS is manufactured and formulated without any animal or human 
proteins, thereby reducing the potential risk of viral contamination in the product.
1.2.2
Pre-Clinical Documentation
The pre-clinical pharmacology-toxicology program has included appropriate toxicology studies to 
support safety for administration of QM1114-DP at the proposed dose of 50 units (U) which will 
be evaluated in this study.
No safety pharmacology or pharmacokinetic studies were conducted for QM1114-DP since no 
systemic exposure to the product is expected with a single IM administration to specific facial 
muscles using the dose proposed.  Additionally, BoNT-A binds with high affinity at the neuronal 
synapses at the local injection site.11 Therefore, any metabolism and elimination of the product 
would occur at the local site of injection.
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1.2.3
Clinical Documentation
CTN 43QM1313
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.
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1.2.4
Dose Rationale
Non-clinical studies have shown a similarity between QM1114-DP potency units and Speywood 
units (Dysport®). Both safety and efficacy for the 30-60 U dose range of QM1114-DP were 
established in the phase 2 study (study CTN 43QM1313). In the treatment of GL with Speywood 
unit products (Dysport®/Azzalure®), the recommended dose is 50 U. Based on the evaluation of 
results for the different dose levels studied to date in the clinical program of QM1114-DP, the 
Sponsor has concluded that a 50 unit dose offers an appropriate balance between efficacy, duration 
of effect and safety.
1.3
Risk/Benefit Assessment
Based on the clinical experience with QM1114-DP, subjects participating in the study may
experience AEs such as injection site reactions and headache (Section 1.2.3). 12
All treating Investigators will be trained in the administration technique of 
QM-1114-DP prior to the study start.  
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The benefit to subjects receiving QM1114-DP in this study will be a temporary reduction in the 
appearance of their GL.  The subjects in the placebo group are not expected to gain any clinical 
benefit from their participation in the study; however, as this is an aesthetic indication there are no 
sequelae to lack of efficacy beyond a disappointment in the reduction of severity of their GL. In 
addition, only one subject out of four will receive placebo in the study.
In the phase 2 study (CTN 43QM1313), QM1114-DP was well tolerated at all dose levels. The 
treatment-related TEAEs reported in the study were of similar type as those reported for other toxins 
in GL treatment. 
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 distant 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 for the treatment of moderate to severe GL appears to offer a 
substantial clinical benefit at reasonable risk.
2.
CLINICAL STUDY OBJECTIVES, ENDPOINTS, AND CLINICAL HYPOTHESIS
2.1
Clinical Study Objectives
The objective of the study is to evaluate the efficacy and safety of a single dose of 50 U of 
QM1114-DP compared to placebo for the treatment of moderate to severe GL.
2.1.1
Primary Efficacy Objectives and Endpoints
The primary efficacy objective is to evaluate a single dose of 50 U of QM1114-DP compared to 
placebo for the treatment of moderate to severe GL.
For primary endpoint, the composite responder rate will be evaluated at Month 1 using GL-ILA and 
GL-SLA at maximum frown. A composite responder is defined as a subject who achieves a score 
of 0 or 1 in glabellar line severity and at least 2 grades improvement from baseline on both the GL-
ILA and GL-SLA scales concurrently. 
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2.1.2
Secondary Efficacy Objective and Endpoints
The secondary efficacy objective and endpoints of the study are:
Objective: To evaluate the efficacy of a single dose of 50 U of QM1114-DP compared to placebo
for the treatment of moderate to severe GL.
Endpoints: 
Percentage of subjects who achieve a score of 0 or 1 at:

Month 1 using the GL-ILA at maximum frown

each post-treatment visit (excluding Month 1) using the GL-ILA at maximum frown at
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2.1.4
Safety Objectives and Endpoints
The safety objective is to evaluate the safety of a single dose of 50 U of QM1114-DP compared to 
placebo for the treatment of moderate to severe GL.
Safety endpoints include:
Incidence and severity of TEAEs
Focused physical examination (FPE) findings
Vital signs
Electrocardiogram (ECG)
Laboratory parameters (clinical chemistry and hematology)
Neutralizing antibody production
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2.2
Clinical Hypothesis
The clinical hypothesis of the study is that QM1114-DP is more effective than placebo for the 
treatment of moderate to severe GL and has an acceptable safety profile.
3.
OVERALL CLINICAL STUDY DESCRIPTION
This is a phase 3, multi-center, randomized, double blind, placebo-controlled study to evaluate the 
efficacy and safety of 50 U of QM1114-DP for the treatment of moderate to severe GL. 
Following the informed consent and the screening process, eligible subjects will be randomly 
assigned in a 3:1 ratio to receive a single treatment at baseline of 50 U QM1114-DP 
(225 subjects) or placebo (75 subjects) in the GL area. Randomization will be stratified by study 
center. 
Each subject will receive a single treatment divided equally among 5 injection points (0.1 mL per 
injection point) in the glabellar region.   
Following treatment at baseline, subjects will be monitored for safety and efficacy according to the 
Schedule of Assessments (Table 2).
Efficacy assessments will include (Section 7.1):

4-point Photographic Scale of GL Severity at 
maximum frown (Investigator 
assessment [GL-ILA])

Static 4-point Categorical Scale of GL Severity at maximum frown (subject assessment 
[GL-SLA])
Safety assessments will include (Section 7.2):

Adverse events (AEs)

FPE

Vital signs

ECG

Laboratory safety tests (chemistry and hematology)
Production of neutralizing antibodies against QM1114-DP
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Selection criteria for the study population are described in Section 5. Detailed information about 
study tasks by study visit is outlined in Section 8 and in Table 2. The study product treatment 
regimen is provided in Section 6 .
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 3 months.
The planned clinical study duration from FSFV to last subject last visit (LSLV) is approximately 
9.5 months.
Clinical study participation for each subject is approximately 6.5 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 study protocol, 
regulation, or 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 percent is anticipated, approximately 330 subjects will 
be screened in order to get 300 subjects enrolled in a 3:1 ratio to QM1114-DP 50 U (N=225) or 
placebo (N=75). 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. Moderate to severe GL (grade of 2 or 3 on the 4-point Photographic Scale ranging from 0 [none] 
to 3 [severe]) at maximum frown as assessed by the Investigator (GL-ILA).
3. Moderate to severe GL (grade of 2 or 3 on the Static 4-Point Categorical Scale ranging from 0 
[no wrinkles] to 3 [severe wrinkles]) at maximum frown as assessed by the subject (GL-SLA).
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4. 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;
Intra uterine 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).
5. Time and ability to complete the study and comply with instructions.
6. 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.
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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 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, botulinumtoxin 
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.
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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.
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.
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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 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.

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 0) 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 0)
should be notified to discuss the subject’s continuation in the clinical study.
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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 6/ 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.

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 7.2.6.2.3. 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.
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6.
CLINICAL SUPPLIES
Details of the drug composition and excipients are provided in the current QM1114-DP Investigators 
Brochure.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 units/mL, buffered solution
N/A, buffer solution
Dosage
50 units
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 (SIN) 
Each study participant who has signed the ICF will be entered into the eCRF system and a subject 
number 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. 
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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.
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 Investigators Brochure. 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
6.2
Study Products(s) Packaging and Labeling
QM1114-DP and placebo are manufactured under aseptic conditions. 
The labels will be printed in English.  The text of the label will detail the information requested by
Good Manufacturing Practice and local regulations, and at a minimum include the protocol number, 
storage conditions, and an investigational test article disclaimer (“Caution: New Drug - Limited by
Federal (or United States) law to investigational use.”)
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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/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 0. A 
PQC is an external judgement presuming a quality defect of a product; quality issue for a product 
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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.
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 7.2.6.2.2).  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 ASSESSMENT
7.1
Efficacy Assessments
7.1.1
4-point Photographic Scale of Glabellar Line Severity: Investigator Live 
Assessment (GL-ILA)
The validated Investigator 4-point Photographic Scale of Glabellar Line Severity (Appendix 1) 
includes two grading systems: one for Investigator live assessments at maximum frown, 
 
. The scale represents the severity of GL from none (grade 0), 
mild (grade 1), moderate (grade 2) to severe (grade 3). Each grade is also depicted by an individual 
photograph and a descriptive text. The Investigators will be trained on the use of the 4-point 
Photographic Scale.
The Investigators will use the 4-point Photographic Scales for direct, live comparison with the 
subject’s face at 
at maximum frown at screening, baseline (prior to treatment), and at all 
post-treatment visits.
7.1.2
Static 4-point Categorical Scale of Glabellar Line Severity: Subject Live 
Assessment (GL-SLA)
Subjects will make their assessment of glabellar line severity independently of the Investigator’s 
assessment. Subjects will be asked to evaluate their GL at maximum frown at screening, baseline 
(prior to treatment), and at all post-treatment visits using the following Static 4-Point Categorical 
Scale.
Grade
Severity of Glabellar Lines
Description
0
No wrinkles
Smooth skin
1
Mild wrinkles
Fairly smooth skin
2
Moderate wrinkles
Frown lines
3
Severe wrinkles
Deep frown lines
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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, FPE, vital signs, ECG, 
laboratory safety tests (chemistry and hematology), 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 physical examination of the subject that includes the face, head, and neck. Further 
details are provided in Appendix 5.
Post-baseline, the signs and symptoms will also be monitored via physical examination of face, head, 
and neck to evaluate local effect of toxin. In addition, general physical examination to evaluate the 
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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 6). 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. Abnormalities noted pre-injection, i.e. at the screening/baseline visits, should be 
recorded as medical history and 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. Vital signs will be taken prior to any blood draw, excluding post-treatment 
measurements on Day 0.
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.
7.2.3
Electrocardiogram (ECG)
The 12-lead ECG recordings will be made after the subjects have been resting in a supine position 
for at least 10 minutes at the time points indicated in Table 2, the baseline ECG should be done prior 
to treatment. The subjects should avoid postural changes during the ECG recordings. At each time-
point, the ECG will be recorded in triplicates. The triplicates will be performed at approximately 
one-minute intervals.
ECGs will be stored electronically and submitted to a central reviewer for analysis. Paper printouts 
may also be collected for general cardiac safety monitoring at the clinical research site.
Clinically significant abnormal values at baseline shall be recorded in the Medical History form. For 
any clinically significant changes from baseline, an AE is to be recorded.
The Investigator and Medical Monitor will be alerted (e.g., email) for ECGs that are identified as 
“abnormal, clinically significant” by the central ECG laboratory.
7.2.4
Laboratory Safety Tests
Blood samples will be collected at baseline (prior to treatment) and at Month 6/ET, and sent to a 
central laboratory for analysis. Instructions for blood sampling are detailed in a separate laboratory 
manual.
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The following laboratory safety tests shall be performed:

Hematology: White blood cell (WBC) count with differential, red blood cell (RBC) count, 
haemoglobin (Hb), hematocrit (hct), and platelet count (Plt)

Blood chemistry: Creatinine, urea nitrogen, gamma glutamyl transferase (GGT), alkaline 
phosphatase (ALP), aspartate aminotransferase (AST=SGOT), alanine aminotransferase 
(ALT=SGPT), and bilirubin (total and conjugated)
The Investigator or a medically qualified sub-Investigator must review and evaluate laboratory
values for each subject in a timely manner.  The Investigator or designee will initial and date all 
laboratory reports and note on the report whether or not an out of range laboratory value is clinically 
significant. An out of range laboratory value should be considered as clinically significant if either 
of the following conditions is met:

The abnormality suggests a disease and/or organ toxicity.

The abnormality is of a degree that requires additional active management, e.g. close 
observation, more frequent follow-up assessments, or further diagnostic investigation.
For each out of range laboratory result, the Investigator or designee will enter directly in the eCRF 
the Investigator judgment on the presence or the absence of a clinical significance.
All clinically significant out-of-range laboratory values for blood samples collected at baseline will 
be recorded in the medical history (report a diagnosis rather than an individual laboratory parameter 
abnormality whenever possible).
All clinically significant out of range laboratory values for blood samples collected after baseline 
are to be reported as an AE if this abnormality was not present at the baseline visit or is assessed as 
having worsened since the baseline visit (i.e., there is a significant change from baseline). 
For AEs, whenever possible, the Investigator is to provide a diagnosis rather than to report individual 
laboratory abnormalities.
7.2.5
Neutralizing Antibody Testing
Subjects will have blood samples taken at baseline prior to treatment, Month 1, and Month 6/ET 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.
7.2.6
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. 
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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.
7.2.6.1
Definitions
7.2.6.1.1
Adverse Events (AE)
According to 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 7.2.6.2.3.

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.
7.2.6.1.2
Treatment Emergent Adverse Event (TEAE)
A TEAE is an event that emerges during or after treatment, having been absent pre-treatment, or 
worsens relative to the pretreatment state.
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7.2.6.1.3
Serious Adverse Events (SAE)
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).
7.2.6.1.4
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., Investigator’s Brochure 
for an unapproved investigational product).
7.2.6.1.5
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.  
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7.2.6.1.6
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.
7.2.6.1.7
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.
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. 
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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.
7.2.6.2
Reporting Procedures
7.2.6.2.1
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. 
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 7.2.6.2.2) and pregnancies (see Section 7.2.6.2.3), 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 7.2.6.2.2).
7.2.6.2.2
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 7.2.6.1.3).
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 
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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 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 Investigator’s Brochure (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.
7.2.6.2.3
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.
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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 0).
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 7.2.6.2.2).
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 photography 
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 6/ET. A negative pregnancy test is required for 
study inclusion. The result will be documented.
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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. The validated 4-point Photographic 
Scale of Glabellar Line Severity has been chosen in agreement with the FDA. 
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 HIPAA and photo 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 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 (including toxin naïve/non-toxin naïve), previous medications 
and procedures, and concomitant medications and procedures (see Table 2
Schedule 
of 
Assessments).
4.
Instruct the subject on how to complete the GL-SLA at maximum frown. Subject to complete 
GL-SLA at maximum frown using the Static 4-point Categorical Scale (Section 7.1.2).
5.
Investigator to complete assessment of the subject’s glabellar line severity at 
maximum frown using the 4-point Photographic Scale (GL-ILA) (Section 7.1.1 and 
Appendix 1).
6.
Investigator to perform a focused PE (Appendix 5). Record abnormal findings as medical 
history. Clinically significant abnormal findings are exclusionary; document as screen fail and 
do not enrolled the subject in the study.
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7.
If the subject is a female of childbearing potential, collect urine for UPT and complete 
pregnancy test (see laboratory manual for additional procedures). Document the result. A 
negative result is required for study inclusion.
8.
Record any AEs on the eCRF. AEs will be collected starting from the time of Informed 
Consent signature.
9.
Review the inclusion/exclusion criteria (Section 5.2.1 and 5.2.2), and confirm if subject meets 
study eligibility requirements. 
If yes, schedule the baseline visit.
If no, document the subject as a screen failure.
10.
For all subjects, enter the subject information into the eCRF; a SIN will be assigned via the 
eCRF system.
8.1.2
Baseline/Visit 2 [Day 0]
If the screening and baseline visits are performed as on same day, only perform study assessments 
once (i.e., AE, concomitant therapies/procedures, UPT, PE, SLA, ILA, inclusion/exclusion review).
A maximum of 14 days is allowed between the screening and baseline visits. 
At the baseline visit, the Investigator or designee will:
1.
Ask the subject about AEs using an open-ended question, such as “Have you noticed any 
change in your health since the last visit?” Record all events, as appropriate.
2.
Ask the subject about any changes in his/her concomitant therapies/procedures (added, 
removed or changed) since the previous visit. Record all changes.
3.
4.
5.
Instruct the subject on how to complete the GL-SLA at maximum frown. Subject to complete 
GL-SLA at maximum frown using the Static 4-point Categorical Scale (Section 7.1.2).
6.
Investigator to complete assessment of the subject’s glabellar line severity at 
maximum frown using the 4-point Photographic Scale (GL-ILA) (Section 7.1.1 and
Appendix 1).
7.
8.
Obtain the subject’s vital signs (blood pressure, heart rate, and respiratory rate). Vital signs 
are to be taken seated after 10 minutes rest (Section 7.2.2). 
9.
Obtain 12-lead ECG recording after the subject has been resting in a supine position for at 
least 10 minutes (Section 7.2.3).
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10.
If the subject is a female of childbearing potential, collect urine for UPT and complete 
pregnancy test (see laboratory manual for additional procedures). Document the result. A 
negative result is required for study inclusion.
11.
Collect blood sample (chemistry and hematology) for analysis at the central laboratory
(Section 7.2.4).
12.
Collect blood sample for neutralizing antibody testing (Section 7.2.5).
13.
Take subject photographs (refer to photo manual for complete instructions). If the subject is 
wearing make-up, instruct the subject to remove it prior to taking photographs.
14.
Investigator to perform a focused PE (Appendix 5). Clinically significant abnormal findings 
are exclusionary; document as screen fail and do not enroll the subject in the study.
15.
Review the inclusion/exclusion criteria (Section 5.2.1 and 5.2.2), and confirm if subject meets 
study eligibility requirements. 
If yes, enroll/randomize the subject in the clinical study. Proceed to next steps.
If no, document the subject as a screen failure.
16.
For all subjects, enter appropriate data into the eCRF; the SIN should have been assigned via 
the eCRF system at the screening visit.
17.
For subjects who meet all eligibility requirements, the Investigator or designee will receive 
notification of the subject’s kit number/randomization assignment once all required data is 
entered into the eCRF. The Investigator or designee should prepare the assigned treatment 
accordingly and complete the required documentation and eCRF (Section 6.1.7).
18.
Prior to injection, clean the subject’s treatment area with a suitable antiseptic solution.
19.
The Investigator will administer the assigned treatment.  See Section 6.1.7.1 for injection 
technique and treatment procedure requirements. Following treatment administration, subjects 
will be monitored at the study center for 30 minutes (Section 6.1.7.2). 
20.
Obtain the subject’s post-treatment vital signs (blood pressure, heart rate, and respiratory rate). 
Vital signs are to be taken seated after 10 minutes rest (Section 7.2.2). 
21.
22.
Ask the subject about AEs using an open-ended question. Record all events, as appropriate, 
on the corresponding eCRF form(s).
23.
Record post-treatment concomitant therapies/procedures.
24.
Schedule the next visit (Day 7 ±1 day).
8.1.3
Day 7/Visit 3 (±1 day)
The Investigator or designee will:
1.
Ask the subject about AEs using an open-ended question, such as “Have you noticed any 
change in your health since the last visit?” Record all events, as appropriate.
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2.
Ask the subject about any changes in his/her concomitant therapies/procedures (added, 
removed or changed) since the previous visit. Record all changes.
3.
4.
Instruct subject on how to complete the SLA at maximum frown. Subject to complete GL-
SLA at maximum frown using the Static 4-point Categorical Scale (Section 7.1.2).
5.
6.
7.
Obtain the subject’s vital signs (blood pressure, heart rate, and respiratory rate). Vital signs 
are to be taken seated after 10 minutes rest (Section 7.2.2). 
8.
Take subject photographs (refer to photo manual for complete instructions). If the subject is 
wearing make-up, instruct the subject to remove it prior to taking photographs.
9.
Investigator to complete assessment of the subject’s glabellar line severity at 
maximum frown using the 4-point Photographic Scale (GL-ILA) (Section 7.1.1 and
Appendix 1).
10.
Investigator to perform a focused PE (Appendix 5). 
11.
Schedule the next visit (Day 14 ±3 days).
8.1.4
Day 14/Visit 4 (±3 days)
The Investigator or designee will:
1.
Ask the subject about AEs using an open-ended question, such as “Have you noticed any 
change in your health since the last visit?” Record all events, as appropriate.
2.
Ask the subject about any changes in his/her concomitant therapies/procedures (added, 
removed or changed) since the previous visit. Record all changes.
3.
Instruct subject on how to complete the SLA at maximum frown. Subject to complete GL-
SLA at maximum frown using the Static 4-point Categorical Scale (Section 7.1.2).
4.
5.
6.
Obtain the subject’s vital signs (blood pressure, heart rate, and respiratory rate). Vital signs 
are to be taken seated after 10 minutes rest (Section 7.2.2). 
7.
Take subject photographs (refer to photo manual for complete instructions). If the subject is 
wearing make-up, instruct the subject to remove it prior to taking photographs.
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8.
Investigator to complete assessment of the subject’s glabellar line severity at 
maximum frown using the 4-point Photographic Scale (GL-ILA) (Section 7.1.1 and
Appendix 1).
9.
Investigator to perform a focused PE (Appendix 5). 
10.
Schedule the next visit (Month 1 ±5 days).
8.1.5
Month 1/Visit 5 (±5 days)
The Investigator or designee will:
1.
Ask the subject about AEs using an open-ended question, such as “Have you noticed any 
change in your health since the last visit?” Record all events, as appropriate.
2.
Ask the subject about any changes in his/her concomitant therapies/procedures (added, 
removed or changed) since the previous visit. Record all changes.
3.
Instruct the subject on how to complete the SLA at maximum frown. Subject to complete GL-
SLA at maximum frown using the Static 4-point Categorical Scale (Section 7.1.2).
4.
5.
6.
7.
8.
Obtain the subject’s vital signs (blood pressure, heart rate, and respiratory rate). Vital signs 
are to be taken seated after 10 minutes rest (Section 7.2.2).
9.
Obtain 12-lead ECG recording after the subject has been resting in a supine position for at 
least 10 minutes (Section 7.2.3).
10.
Collect blood sample for neutralizing antibody testing.
11.
Take subject photographs (refer to photo manual for complete instruction). If the subject is 
wearing make-up, instruct the subject to remove it prior to taking photographs.
12.
Investigator to complete assessment of the subject’s glabellar line severity at 
maximum frown using the 4-point Photographic Scale (GL-ILA) (Section 7.1.1 and
Appendix 1).
13.
Investigator to perform a focused PE (Appendix 5).
14.
Schedule the next visit (Month 2 ±5 days).
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8.1.6
Months 2-5/Visit 6-9 (±5 days)
The Investigator or designee will:
1.
Ask the subject about AEs using an open-ended question, such as “Have you noticed any 
change in your health since the last visit?” Record all events, as appropriate.
2.
Ask the subject about any changes in his/her concomitant therapies/procedures (added, 
removed or changed) since the previous visit. Record all changes.
3.
Instruct subject on how to complete the SLA at maximum frown. Subject to complete GL-
SLA at maximum frown using the Static 4-point Categorical Scale (Section 7.1.2).
4.
5.
6.
7.
Take subject photographs (refer to photo manual for complete instructions). If the subject is 
wearing make-up, instruct the subject to remove it prior to taking photographs.
8.
Investigator to complete assessment of the subject’s glabellar line severity at 
maximum frown using the 4-point Photographic Scale (GL-ILA) (Section 7.1.1 and
Appendix 1).
9.
Schedule the next monthly visit (± 5 days).
8.1.7
Month 6/Visit 10 or Early Termination visit (±5 days)
At the Final/ET, the Investigator or designee will:
1.
Ask the subject about AEs using an open-ended question, such as “Have you noticed any 
change in your health since the last visit?” Record all events, as appropriate.
2.
Ask the subject about any changes in his/her concomitant therapies/procedures (added, 
removed or changed) since the previous visit. Record all changes.
3.
Instruct subject on how to complete the SLA at maximum frown. Subject to complete GL-
SLA at maximum frown using the Static 4-point Categorical Scale (Section 7.1.2).
4.
5.
6.
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7.
8.
Obtain the subject’s vital signs (blood pressure, heart rate, and respiratory rate). Vital signs 
are to be taken seated after 10 minutes rest (Section 7.2.2). 
9.
Obtain 12-lead ECG recording after the subject has been resting in a supine position for at 
least 10 minutes (Section 7.2.3). 
10.
Collect blood sample (chemistry and hematology) for analysis at the central laboratory.
11.
Collect blood sample for neutralizing antibody testing.
12.
Take subject photographs (refer to photo manual for complete instructions). If the subject is 
wearing make-up, instruct the subject to remove it prior to taking photographs.
13.
If the subject is a female of childbearing potential, collect urine for UPT and complete 
pregnancy test (see laboratory manual for additional procedures). Document the result.
14.
Investigator to complete assessment of the subject’s glabellar line severity at 
maximum frown using the 4-point Photographic Scale (GL-ILA) (Section 7.1.1 and 
Appendix 1).
15.
Investigator to perform a focused PE (Appendix 5). 
16.
Exit the subject from the study.
8.2
Unscheduled Visits
When necessary, unscheduled visits may be conducted, in particular if an AE occurs and needs to 
be assessed and/or treated.
8.3
Subject Instructions
Subjects will be advised that any facial make-up will need to be removed before taking study
photographs. 
Subjects will also be advised of post-treatment care instructions as outlined in Section 6.1.7.2.
9.
STATISTICAL METHODS PLANNED
9.1
Statistical and Analytical Plans
A Statistical Analysis Plan (SAP) will be developed as a separate document. The SAP will contain 
a more detailed and technical description of specific data conventions, calculations and of statistical 
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procedures for executing the analyses that are specified in the sections of the clinical study protocol 
below. The SAP will be finalized prior to database lock.
A separate SAP for EU will be created. The EU SAP will include a responder definition for the 
primary endpoint according to the EU requirement.
Any change made to the finalized SAP will be documented in the Clinical Study Report (CSR).
9.1.1
Data Transformations
For antibody testing results, log transformation might be used as necessary.
9.1.2
Populations Analyzed and Evaluability 
The statistical analyses will be performed based on the following subject populations.
9.1.2.1
Modified Intent-to-treat (mITT) Efficacy Population
The modified Intention-to-treat (mITT) population includes all subjects who are randomized and 
dispensed the investigational product, and will be analyzed according to the randomization scheme; 
subjects with a photographic and categorical scale Month 1 assessment via a remote visit will be 
excluded from the mITT. The mITT population will be used for primary efficacy analysis. 
9.1.2.2
Intent-to-treat (ITT) Efficacy Population
The Intention-to-treat (ITT) population includes all subjects who are randomized and dispensed the 
investigational product, and will be analyzed according to the randomization scheme. All secondary
efficacy
variables will be analyzed based on the ITT population, as well as a 
sensitivity analysis of the primary efficacy endpoint.
9.1.2.3
Per-protocol (PP) Efficacy Population
The Per Protocol (PP) population is a subset of the mITT subjects who have no protocol deviations 
that are considered to have a substantial impact on the primary efficacy outcome. If the PP
population contains less than 90% of the subjects in mITT, a sensitivity analysis of the primary 
efficacy endpoint will be performed based on the PP population.  
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9.1.2.4
Safety Population
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.
9.1.2.5
Imputation of Missing Data
The Observed Cases (OC) will be used for all safety analyses as well as the secondary
efficacy analyses. The primary efficacy analysis will be performed using multiple 
imputation (MI), and repeated using baseline observation carried forward (BOCF) for missing 
values. If deemed necessary, any analyses may be repeated using OC, BOCF, or MI as appropriate.
9.1.3
Data Presentation and Graphics
All statistical analyses, including summary tables and data listings, will be performed using the 
SAS® system (version 9).
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 plots 
and estimates of the median event times will be used.
9.1.3.1
Subgroup Analysis
Analysis on the proportion of composite responders at Month 1 as measured by the ILA and the 
SLA at maximum frown will be performed in the following subgroups:

Gender

Baseline severity score of the ILA of GL at maximum frown

Previous treatment with BoNT-A

Fitzpatrick skin type
For duration of response, a subgroup analysis using only subjects with at least 2 point improvement 
on the GL-ILA will be conducted. Thus, duration of response will be analyzed based on the full ITT 
population as well as a subgroup analysis.
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9.1.3.2
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 SOC and 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 these presentations will be provided.
AEs occurring before treatment will only be provided in subject data listings.
Data for hematology, blood chemistry, antibodies, and vital signs will be summarized by descriptive 
statistics with the value at each visit as well as the change from baseline. Results of ECGs will be 
summarized descriptively. The results of the urine pregnancy tests will be listed.
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 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.
9.1.5
Inferential Statistical Analyses
The primary efficacy endpoint will be a composite responder rate based on the GL-ILA and GL-
SLA assessments of glabellar line severity at maximum frown at Month 1. Responder is defined as 
a subject who achieves a score of 0 or 1 and at least 2 grades improvement from baseline, on both 
scales concurrently. 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 thus be compared using 
Cochran-Mantel-Haenszel test, stratified by center, at 5% significance level (2-sided). Depending 
on the number of centers, pooling of centers might 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.
The analysis of the primary efficacy endpoint will be based on the mITT population.  A sensitivity
analysis of the primary efficacy endpoint will be performed using the ITT population.
For the secondary endpoints, the Cochran-Mantel-Haenszel test will be used to compare the 
proportion of subjects who achieve 0 or 1 on the GL-ILA at maximum frown at Month 1 and at all 
the rest of the post-treatment visits. To control the type I error rate, the fixed sequence testing 
procedure will be used, which requires no adjustment to the level of significance. However the 
comparisons must be made in a pre-specified order following the procedure outlined below:
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1. Primary analysis
Secondary analysis:
2. Month 1
3. Day 14
4. Month 2
5. Month 3
6. Month 4
7. Month 5
8. Month 6
9. Day 7
If one of the tests in the sequence is not significant (p > 0.05), no confirmatory claims can be made 
based on tests following (and including) that one.
The secondary analysis in the sequence will be based on the ITT population with the remote visit 
assessments excluded. A sensitivity analysis will be run using the ITT population including the 
remote visit assessments.  
9.2
Sample Size Determination
The sample size is determined by the number of subjects exposed to QM1114-DP in the GL, and 
amount of long-term safety data. 
Further, due to the public health emergency related to the COVID-19 pandemic during 2020, steps 
have been taken to ensure patient and practitioner safety in alignment with FDA Guidance dated 
May 11, 2020 (Guidance on Conduct of Clinical Trials of Medical Products during COVID-19 
Public Health Emergency). Most notably, in partnership with clinical sites and the IRB, optional 
remote assessment procedures for efficacy and safety endpoints has been implemented to ensure 
safety and respect localized and elective restrictions. However, the number of subjects in the mITT 
population used in the assessment of the primary efficacy endpoint, should still satisfy the sample 
size requirements for the primary efficacy analysis.
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9.2.3
Sample Size Calculation
The study is planned to include approximately 300 subjects, of whom 225 will be treated with 
QM1114-DP and 75 subjects will receive placebo.
9.2.4
Interim Analysis
Not applicable.  An interim analysis is not planned for this study.
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 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.
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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, ICH-GCP guidelines, and applicable SOPs.  
The Investigator will allow the CRO/Sponsor’s representatives, to have direct access to all clinical 
study records, CRFs, 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 
CRF 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 and if applicable AE of special interest) 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.
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 SOPs for clinical study conduct and monitoring from the Sponsor and/or the 
Contract Research Organization (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/IECs before, during, 
or after the clinical study.  
The Investigator will allow and assist the CRO/Sponsor’s representatives, IRBs/IECs and any 
regulatory agency to have direct access to all requested clinical study-related records.
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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/IEC 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 or the 
Ethics Committees. 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
Independent Ethics Committee (IEC) or Institutional Review Board (IRB)
This clinical study protocol and all applicable amendments will be reviewed and approved by the 
appropriate IECs/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 consent), approved by an IRB/IEC, 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 (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 Principal Investigator 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 Principal Investigator are responsible 
for complying with all requirements pursuant to national legislation in the country in which the 
Institution and Principal Investigator are located.
The Principal Investigator understands that clinical studies conducted under an IND are exempt from 
the study subject identifier confidentiality provisions of the Health Insurance Portability and Access 
Act of 1996 (HIPAA), as provided at 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 Principal Investigator 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 Principal Investigator 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 
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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.
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.
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If the Principal Investigator 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.
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 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:
Medical Monitor:
Safety e-mail for SAE, 
Pregnancy Reporting, and 
PQC:
E-mail:
CRO:
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12.
Summary of Changes in Clinical Study Protocol 43QM1602 
12.1
Protocol Version 3.0 to Version 4.0
Remote assessment procedures for efficacy and safety endpoints to ensure safety and respect 
localized and elective restrictions were implemented due to COVID-19 pandemic. Therefore, the 
modified Intention-to-treat (mITT) efficacy population is added to the statistical analyses for 
primary efficacy analysis. This action affect several sections of the Protocol as summarized below.
Section in the clinical 
study protocol
Rational for changes
Description of changes
Section 9.1.1, Data 
Transformations
Clarification
Section 9.1.2.1, 
Populations Analyzed 
and Evaluability;
List of abbreviations and 
definitions of terms
Due 
to 
COVID-19 
pandemic 
actions.
The mITT efficacy population will 
be used for assessment of the 
primary efficacy endpoint. Subjects 
with a photographic and categorical 
scale Month 1 assessment via a 
remote visit will be excluded from 
the mITT
Modified 
Intent-to-treat 
(mITT) 
Efficacy Population added (primary 
efficacy analysis).
Section 9.1.2.2, Intent to 
treat (ITT) Efficacy 
Population
Due 
to 
COVID-19 
pandemic 
actions.
The mITT population will be used for 
primary 
efficacy 
analysis. 
A 
sensitivity analysis of the primary 
efficacy endpoint will be based on the 
ITT population.
Section 9.1.2.3, Per-
protocol (PP) Efficacy 
Population
Clarification due to COVID-19 
pandemic actions.
Changed from “ITT” to “mITT”
Section 9.1.2.5, 
Imputation    of Missing 
Data
Due 
to 
COVID-19 
pandemic 
actions. 
An increased number of drop-outs/ 
missing data at Month 1 visit.
Primary imputation changed to “MI” 
instead of “BOCF”.
Section 9.1.5, Inferential 
Statistical Analyses
Clarification due to COVID-19 
pandemic actions.
Added:
“The analysis of the primary efficacy 
endpoint will be based on the mITT 
population.  A sensitivity analysis of 
the primary efficacy endpoint will be 
performed using the ITT population.”
“The secondary analysis in the 
sequence will be based on the ITT 
population with the remote visit 
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Section in the clinical 
study protocol
Rational for changes
Description of changes
assessments excluded. A sensitivity 
analysis will be run using the ITT 
population including the remote visit 
assessments.”  
Section 9.2, Sample Size 
Determination
Clarification due to COVID-19 
pandemic actions.
Added:
“The sample size is determined by the 
number of subjects exposed to 
QM1114-DP in the GL, and amount of 
long-term safety data.”
“Further, due to the public health 
emergency related to the COVID-19 
pandemic during 2020, steps have 
been taken to ensure patient and 
practitioner safety in alignment with 
FDA Guidance dated May 11, 2020 
(Guidance on Conduct of Clinical 
Trials of Medical Products during 
COVID-19 
Public 
Health 
Emergency). 
Most 
notably, 
in 
partnership with clinical sites and the 
IRB, optional remote assessment 
procedures for efficacy and safety 
endpoints has been implemented to 
ensure safety and respect localized and 
elective restrictions. However, the 
number of subjects in the mITT 
population used in the assessment of 
the primary efficacy endpoint, should 
still 
satisfy 
the 
sample 
size 
requirements for the primary efficacy 
analysis.”
Section 12: Section 12.1
Protocol Amendment
Added Section: Summary of Changes 
Protocol version 3.0 to version 4.0
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13.
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. Investigators Brochure QM1114-DP (Botulinum Neurotoxin Type A) Upper Facial Wrinkles, edition 5.
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), 
2004.
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14.
APPENDICES
Appendix 1
Validated Investigator 4-point Photographic Scale of Glabellar Line Severity 
(GL-ILA)
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Appendix 5
Focused Physical Examination Form Example
Not done  
     Provide details: _____________________________________________________
General Health Assessment: Complete at Screening, Baseline (prior to treatment), Day 7, Day 14, and Months 1, 
and 6/ET
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 6). 
Abnormalities noted pre-injection should be recorded as medical history and Investigator should confirm if any 
abnormalities affect subject eligibility. 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), Day 7, Day 14, and Months 1, and 6/ET
Please perform a targeted examination of the face, head, and neck recording abnormalities. 
Part 1 Examination
Normal
Abnormal* (provide details)
Eyelid position
Eyebrow position
Vision abnormalities (not 
refractive errors)
Throat function (e.g., 
swallowing/drink water)
Ability to talk and chew
Ability to stick out and move 
tongue
Ability to lift shoulders 
* Abnormal findings at the screening and baseline visit, noted pre-injection, should be recorded as medical 
history and the Investigator should confirm if any abnormalities affect subject eligibility. Abnormalities noted 
after study treatment should be documented as AEs.
__________________________________
______________________
Investigator Signature
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PART 2: Complete Day 7, Day 14, and Months 1, and 6/ET
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 6) 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? 
* Abnormalities should be documented as AE.
Additional comments for Focused Physical Exam: 
_______________________________________________________________________________________________
_______________________________________________________________________________________________
____________________________________________________________________________________________
__________________________________
______________________
Investigator Signature
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Appendix 6
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
CTN:
43QM1602
CSP title:
A Multicenter, Randomized, Double-Blind, Placebo-Controlled 
Study to Evaluate the Efficacy and Safety of QM1114-DP for the 
Treatment of Moderate to Severe Glabellar Lines (READY - 1)
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
2020-06-10 07:51
Justification
Approved by Technical Expert
2020-06-10 08:26
Justification
Approved by Technical Expert
2020-06-10 11:34
Justification
Compiled by
2020-06-11 08:02
Justification
Approved by Owner
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PPD
PPD
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PPD