A Phase 2 Multicenter, Randomized, Double-Blind, Placebo-Controlled, Dose-Ranging Study to Evaluate the Safety and Efficacy of BOTOX® (Botulinum Toxin Type A) Purified Neurotoxin Complex for the Treatment of Platysma Prominence
Phase: PHASE2
Conditions: Platysma Prominence
Sponsor: Allergan



 
 
Approval Date: 
 
12-Aug-2019
 
CONFIDENTIAL 
Protocol 1936-201-008 Amd 1
BOTOX 
 
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Table of Contents 
Title Page ........................................................................................................................................1 
Protocol Amendment Summary of Changes Table .........................................................................2 
Table of Contents ...........................................................................................................................3 
List of Tables ..................................................................................................................................5 
List of Figures .................................................................................................................................6 
1. 
Protocol Summary ..........................................................................................................7 
1.1. 
Synopsis ............................................................................................................................7 
1.2. 
Schedule of Activities (SoA) ..........................................................................................10 
2. 
Introduction ...................................................................................................................12 
2.1. 
Study Rationale ...............................................................................................................12 
2.2. 
Background .....................................................................................................................12 
2.3. 
Benefit/Risk Assessment ................................................................................................14 
3. 
Objectives and Endpoints ............................................................................................16 
4. 
Study Design ..................................................................................................................17 
4.1. 
Overall Design ................................................................................................................17 
4.2. 
Scientific Rationale for Study Design ............................................................................17 
4.3. 
Justification for Dose ......................................................................................................18 
4.4. 
End of Study Definition ..................................................................................................19 
5. 
Study Population ...........................................................................................................20 
5.1. 
Inclusion Criteria ............................................................................................................20 
5.2. 
Exclusion Criteria ...........................................................................................................21 
5.3. 
Lifestyle Considerations .................................................................................................24 
5.4. 
Screen Failures ................................................................................................................24 
6. 
Study Intervention ........................................................................................................25 
6.1. 
Study Intervention Administered ....................................................................................25 
6.2. 
Preparation/Handling/Storage/Accountability ................................................................27 
6.3. 
Measures to Minimize Bias: Randomization and Blinding ............................................28 
6.4. 
Study Intervention Compliance ......................................................................................29 
6.5. 
Concomitant Therapy .....................................................................................................29 
6.5.1. 
Prohibited Interventions and Washout Before the Study ................................................29 
6.5.2. 
Permitted Interventions ...................................................................................................29 
6.5.3. 
Prohibited Interventions During the Study .....................................................................30 
6.6. 
Dose Modification ..........................................................................................................30 
6.7. 
Intervention after the End of the Study ...........................................................................30 
7. 
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal........................................................................................30 

 
 
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7.1. 
Discontinuation of Study Intervention ............................................................................31 
7.2. 
Participant Discontinuation/Withdrawal from the Study ................................................31 
7.3. 
Lost to Follow Up ...........................................................................................................32 
8. 
Study Assessments and Procedures.............................................................................32 
8.1. 
Efficacy Assessments .....................................................................................................33 
8.1.1. 
Primary Efficacy Assessment .........................................................................................33 
8.1.2. 
Secondary Efficacy Assessment .....................................................................................33 
8.1.3. 
Exploratory Efficacy Assessments .................................................................................34 
8.2. 
Safety Assessments .........................................................................................................36 
8.2.1. 
Height and Weight ..........................................................................................................36 
8.2.2. 
Vital Signs .......................................................................................................................36 
8.2.3. 
Pregnancy Testing ...........................................................................................................36 
8.3. 
Adverse Events and Serious Adverse Events .................................................................36 
8.3.1. 
Time Period and Frequency for Collecting Adverse Event and 
Serious Adverse Event Information ................................................................................37 
8.3.2. 
Method of Detecting Adverse Events and Serious Adverse 
Events ..............................................................................................................................37 
8.3.3. 
Follow-up of Adverse Events and Serious Adverse Events ...........................................37 
8.3.4. 
Regulatory Reporting Requirements for Serious Adverse Events ..................................38 
8.3.5. 
Pregnancy ........................................................................................................................38 
 
 
8.3.7. 
Medication Errors ...........................................................................................................39 
8.4. 
Treatment of Overdose ...................................................................................................39 
8.5. 
Pharmacokinetics ............................................................................................................40 
8.6. 
Pharmacodynamics .........................................................................................................40 
8.7. 
Genetics ..........................................................................................................................40 
8.8. 
Biomarkers and Other Assessments ...............................................................................40 
8.9. 
Health Economics ...........................................................................................................40 
9. 
Statistical Considerations .............................................................................................40 
9.1. 
Statistical Hypotheses .....................................................................................................40 
9.2. 
Sample Size Determination ............................................................................................41 
9.3. 
Populations for Analyses ................................................................................................41 
9.4. 
Statistical Analyses .........................................................................................................42 
9.4.1. 
Efficacy Analyses ...........................................................................................................42 
9.4.2. 
Safety Analyses ...............................................................................................................43 
9.4.3. 
Other Analyses ................................................................................................................44 
9.5. 
Interim Analyses .............................................................................................................44 
10. 
Supporting Documentation and Operational Considerations ..................................45 
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations ................................................................................................................45 
10.1.1. Regulatory and Ethical Considerations ...........................................................................45 
10.1.2. Financial Disclosure ........................................................................................................45 

 
 
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Table 9-3 
Multiple Comparisons Procedure ...................................................................... 42 
Table 10–1 
Highly Effective and Acceptable Contraceptive Methods ................................ 62 
 
List of Figures 
Figure 2-1 
The Platysma Muscle: Anterior and Posterior Margins of the Platysma Muscle 
Sheets ................................................................................................................ 14 
 
 
 

 
 
 
 
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1.2. 
Schedule of Activities (SoA) 
Procedures are recommended to be done in sequence as listed in the schedule below, unless otherwise stated. 
 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
Visits 7 
Visit 8 
Study Procedures 
Screening 
Day -14 
to Day -7 
Baseline/ 
Randomization/ 
Intervention 
Day 1a 
Day 7 
Day 14 
Day 30 
Day 60 
Day 90 
Study 
Exitb 
Day 120 
Visit Windows 
- 
- 
± 3 Days 
± 3 Days 
± 3 Days 
± 7 Days 
± 7 Days 
± 7 Days 
Informed Consent, Privacy Authorization 
X 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
X 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
Medical/Surgical History 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
Weight  
X 
X 
X 
X 
X 
X 
X 
X 
Fitzpatrick Skin Phototyped 
X 
 
 
 
 
 
 
 
Abbreviated Physical Examinatione  
X 
 
 
 
 
 
 
 
Vital Signsf 
X 
X 
X 
X 
X 
X 
X 
X 
Urine Pregnancy Test (WOCBP only)g 
X 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
Standardized Photography 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
Self-Assessment by Participants: 
 
 
 
 
 
 
 
 
     Participant Allergan Platysma Prominence Scale (P-APPS)i 
 
X 
X 
X 
X 
X 
X 
X 
     
 
 
 
 
 
 
 
 
 
     
 
 
 
 
 
 
 
 
 
     
 
 
 
 
 
 
 
 
 
     
 
 
 
 
 
 
 
 
 
     
 
 
 
 
 
 
 
     
 
 
 
 
 
 
 
 
 
     
 
 
 
 
 
 
 
 
 

 
 
 
 
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Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
Visits 7 
Visit 8 
Study Procedures 
Screening 
Day -14 
to Day -7 
Baseline/ 
Randomization/ 
Intervention 
Day 1a 
Day 7 
Day 14 
Day 30 
Day 60 
Day 90 
Study 
Exitb 
Day 120 
Visit Windows 
- 
- 
± 3 Days 
± 3 Days 
± 3 Days 
± 7 Days 
± 7 Days 
± 7 Days 
     
 
 
 
 
 
 
 
 
 
     
 
 
 
 
 
 
 
 
 
     
 
 
 
 
 
 
 
 
 
     
 
 
 
 
 
 
 
 
 
Clinician Assessment: 
 
 
 
 
 
 
 
 
     Clinician Allergan Platysma Prominence Scale (C-APPS) 
X 
X 
X 
X 
X 
X 
X 
X 
Randomization 
 
X 
 
 
 
 
 
 
Study Intervention Administrationj 
 
X 
 
 
 
 
 
 
Concomitant Medications/Procedures 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Eventsk 
X 
X 
X 
X 
X 
X 
X 
X 
a 
All baseline (Day 1) study procedures, including patient-reported outcome questionnaires, must be completed before randomization and study intervention.  
b 
Or early discontinuation from the study. All exit assessments should be completed as soon as possible after a decision to discontinue a participant from the study. 
c 
 
d 
Fitzpatrick Skin Phototype is provided in Section 10.11. 
e 
An abbreviated physical examination will be completed at the screening visit and will include the investigator assessment of general appearance, head, ears, eyes, nose, throat (HEENT), and 
neck. 
f 
Vital Signs (blood pressure, respiratory rate, pulse rate) will be taken while the participant is sitting for at least 5 minutes.  
g 
Woman of childbearing potential (WOCBP) must have a negative urine test result before receiving study intervention. A urine pregnancy test may also be performed at any other visit, at the 
investigator’s discretion.  
h 
 
 
  
j 
Prepared by an Independent Drug Reconstitutor (IDR) and injected by the investigator. NOTE:  The IDR must not perform any other study-related procedures.  
k 
On Day 1, AEs will be collected prior to and after treatment. Participants will be observed at least 30 minutes after study intervention administration for AEs. In the case of an AESI, see 
Section 8.3.6. 
 
 

 
 
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Table 6-2 
Study Formulations and Dilution Instructions 
Study Intervention 
Name 
BOTOX High Dose 
BOTOX Low Dose 
Placebo 
Packaging and 
Labeling 
Each study kit will have one vial containing 100 U of freeze-dried 
powder. 
Each vial will be labeled as required per country requirement. 
The high and low dose BOTOX study kits will look identical. 
Placebo vials will be supplied 
in kits with identical 
appearance to kits containing 
BOTOX vials. 
Each placebo vial will be 
labeled as required per country 
requirement. 
Manufacturer 
Allergan 
 
6.2. 
Preparation/Handling/Storage/Accountability 
1. The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study intervention received and any discrepancies are 
reported and resolved before use of the study intervention. 
2. Only participants enrolled in the study may receive study intervention. Only the sponsor may 
supply the study intervention; only the Independent Drug Reconstitutor (IDR) may prepare 
the study intervention; and only the investigator, trained in the study-specific injection 
technique, may administer study intervention. All study intervention must be stored in a 
secure, environmentally controlled, and monitored (manual or automated) area in accordance 
with the labeled storage conditions with access limited to the investigator and authorized site 
staff. 
3. The IDR is responsible for study intervention accountability, reconciliation, and record 
maintenance (ie, receipt, reconciliation, and final disposition records).  
4. Further guidance and information for the final disposition of unused study interventions are 
provided in the Study Pharmacy Manual.  

 
 
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assignment is unblinded, the sponsor must be notified within 24 hours after breaking the blind. 
The date and reason that the blind was broken must be recorded in the source documentation. 
6.4. 
Study Intervention Compliance 
Participants will receive a single treatment of BOTOX under the direct supervision of study site 
personnel.  
The study site will keep an accurate drug disposition record that specifies the amount of study 
intervention administered to each participant and the date of administration. 
6.5. 
Concomitant Therapy 
Study center staff must notify the sponsor immediately if a participant consumes any 
concomitant medications not permitted by the protocol. Participants who admit to using 
prohibited concomitant medications may be discontinued from the study at the discretion of the 
investigator or the sponsor. 
The use of any concomitant medication or vaccine, (including prescription or over-the-counter 
medication, vitamins and/or herbal supplements), is to be recorded on the participant’s eCRF at 
each visit along with the reason the medication is taken. 
Concomitant therapy and/or medications considered necessary for the study participant’s welfare 
may be given at the discretion of the investigator. 
If concomitant medications may have an effect on efficacy or safety outcomes, these medications 
should be administered in dosages that remain constant throughout the course of the trial at the 
discretion of the investigator. 
If the permissibility of a specific medication/treatment is in question, please contact the sponsor. 
6.5.1. 
Prohibited Interventions and Washout Before the Study 
Refer to eligibility criteria (exclusion criteria, Section 5.2 ). 
6.5.2. 
Permitted Interventions 
Any medication or vaccine (including over-the-counter or prescription medicines, vitamins, 
and/or herbal supplements) that the participant is receiving at the time of enrollment or receives 
during the study must be recorded along with: 
• Indication/reason for medication use 
• Dates of administration including start and end dates 
• Dosage information including dose and frequency 
Therapy considered necessary for the participant’s welfare may be given at the discretion of the 
investigator. If the permissibility of a specific concomitant or prior medication/treatment is in 
question, please contact the sponsor. 

 
 
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Notification of early participant discontinuation from the study and the reason for 
discontinuation will be made to the sponsor and will be clearly documented in the appropriate 
eCRF.  
The sponsor should be consulted in advance of withdrawal whenever possible. Every effort 
should be made to retain participants in the study until completion as much as possible. 
Participants who are withdrawn from the study may not be re-enrolled but will be asked to 
undergo all early withdrawal activities. Definitions of the standard terms are provided in 
Appendix 5.  
Reasons for discontinuation from the study treatment and/or the study may include the following 
commonly used or other acceptable terms: 
Commonly Used Terms 
Other Acceptable Terms 
Adverse event 
Death 
Completed 
 
Lost to follow-up 
 
Other 
 
Physician decision 
 
Pregnancy 
 
Protocol deviation 
 
Screen failure 
 
Site terminated by sponsor 
 
Study terminated by sponsor 
 
Withdrawal by subject 
 
 
7.1. 
Discontinuation of Study Intervention 
If a participant does not tolerate study injections, the participant will be observed until the 
intolerability has either resolved or satisfactorily stabilized in the judgement of the investigator 
and the participant may choose to exit the study or to remain in the study for all safety follow-up 
assessments through the EOS Visit. 
If a pregnancy is confirmed after the participant has received study intervention, the participant 
may choose to exit the study after appropriate safety follow-up or to remain in the study for all 
safety and efficacy follow-up assessments through the EOS visit.  
7.2. 
Participant Discontinuation/Withdrawal from the Study 
• A participant may withdraw from the study at any time at his/her own request or may be 
withdrawn at any time at the discretion of the investigator for safety, behavioral, compliance, 
or administrative reasons. 

 
 
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• If the participant withdraws consent for disclosure of future information, the sponsor may 
retain and continue to use any data collected before such a withdrawal of consent. 
• See the SoA for data to be collected at the time of study discontinuation and follow-up and 
for any further evaluations that need to be completed. 
7.3. 
Lost to Follow Up 
A participant will be considered lost to follow-up if he/she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site. 
The following actions must be taken if a participant fails to return to the clinic for a required 
study visit: 
• The site must attempt to contact the participant and reschedule the missed visit as soon as 
possible and counsel the participant on the importance of maintaining the assigned visit 
schedule and ascertain whether or not the participant wishes to and/or should continue in the 
study. 
• Before a participant is deemed lost to follow-up, the investigator or designee must make 
every effort to regain contact with the participant (where possible, 3 telephone calls and, if 
necessary, a certified letter to the participant’s last known mailing address or local equivalent 
methods). These contact attempts will be documented in the participant’s medical record. 
• Should the participant continue to be unreachable, he/she will be considered to have 
withdrawn from the study. 
8. 
Study Assessments and Procedures 
• Study procedures and their timing are summarized in the SoA (Section 1.2).  
• Protocol waivers or exemptions are not allowed. 
• Immediate safety concerns should be discussed with the sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or discontinue study 
intervention. 
• Adherence to the study design requirements, including those specified in the schedule of 
assessments, is essential and required for study conduct. 
• All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable. During the Screening Period, the investigator or 
subinvestigator will assess the clinical significance of any physical examination findings. 
Any participants with abnormalities judged to meet exclusion criteria will be excluded from 
the study. 

 
 
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The investigator and any qualified designees are responsible for collecting, detecting, 
documenting, and recording events that meet the definition of an AE or SAE and any other 
study-specific term as relevant and remain responsible for following up AEs that are serious, 
considered related to the study intervention or study procedures, or that caused the participant to 
discontinue the study (see Section 7). 
8.3.1. 
Time Period and Frequency for Collecting Adverse Event and Serious Adverse 
Event Information 
All SAEs from the signing of the ICF until the follow-up visit will be collected at the timepoints 
specified in the SoA (Section 1.2), and as observed or reported spontaneously by study 
participants. 
All AEs from the signing of the ICF until the follow-up visit will be collected at the timepoints 
specified in the SoA (Section 1.2), and as observed or reported spontaneously by study 
participants. 
Medical occurrences that begin before the start of study intervention, but after obtaining 
informed consent will be recorded in the AE section of the eCRF. 
All SAEs will be recorded and reported to the sponsor or designee within 24 hours of awareness, 
as indicated in Appendix 3. The investigator will submit any updated SAE data to the sponsor 
within 24 hours of it being available.  
AESIs are described below in Section 8.3.6 and in Appendix 3. 
Investigators are not obligated to actively seek AE or SAE information after conclusion of the 
study participation. However, if the investigator learns of any SAE, including a death, at any 
time after a participant has been discharged from the study, and he/she considers the event to be 
reasonably related to the study intervention or study participation, the investigator must promptly 
notify the sponsor. 
The method of recording, evaluating, and assessing causality of AEs and SAEs and the 
procedures for completing and transmitting SAE reports are provided in Appendix 3. 
8.3.2. 
Method of Detecting Adverse Events and Serious Adverse Events 
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
non-leading verbal questioning of the participant is the preferred method to inquire about 
AE occurrences. 
8.3.3. 
Follow-up of Adverse Events and Serious Adverse Events 
After the initial AE/SAE report, the investigator is required to proactively follow each participant 
at subsequent visits/contacts. All SAEs and AESI (as defined in Section 8.3.6) will be followed 
until resolution, stabilization, the event is otherwise explained, or the participant is lost to follow-
up (as defined in Section 7.3). 

 
 
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The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by the sponsor to 
elucidate the nature and/or causality of the AE or SAE as fully as possible. This may include 
additional laboratory tests or investigations, histopathological examinations, or consultation with 
other health care professionals. 
If a participant dies during participation in the study or during a recognized follow-up period, the 
investigator will provide the sponsor with a copy of any postmortem findings including 
histopathology. 
New or updated information will be recorded in the originally completed eCRF. 
The investigator will submit any updated SAE data to the sponsor within 24 hours of receipt of 
the information. 
8.3.4. 
Regulatory Reporting Requirements for Serious Adverse Events 
• Prompt notification by the investigator to the sponsor of an SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of a 
study intervention under clinical investigation are met. 
• The sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study intervention under clinical investigation. The 
sponsor will comply with country-specific regulatory requirements relating to safety 
reporting to the regulatory authority, IRBs/ IECs, and investigators. 
• Investigator safety reports must be prepared for SUSARs according to local regulatory 
requirements and sponsor policy and forwarded to investigators as necessary. 
• An investigator who receives an investigator safety report describing an SAE or other 
specific safety information (eg, summary or listing of SAEs) from the sponsor will review 
and then file it along with the IB and will notify the IRB/IEC, if appropriate according to 
local requirements. 
8.3.5. 
Pregnancy 
• 
Details of all pregnancies in female participants will be collected after the start of study 
intervention and until the EOS. 
• 
If a pregnancy is reported, the investigator should inform the sponsor within 24 hours of 
learning of the pregnancy and should follow the procedures outlined in Appendix 7. 
• 
Abnormal pregnancy outcomes (eg, spontaneous or elective abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAEs. 
 
 
  

 
 
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• The safety population includes all randomized participants who are administered study 
intervention. Participants will be summarized according to the study intervention they 
received. 
9.4. 
Statistical Analyses 
The SAP and PRO SAP for psychometric analysis will be developed and finalized before 
database lock and will describe the participant populations to be included in the analyses, and 
procedures for accounting for missing, unused, and spurious data. This section summarizes the 
main features of the planned statistical analyses of the primary and secondary endpoints. 
9.4.1. 
Efficacy Analyses 
9.4.1.1. 
Primary and Secondary Endpoints 
The primary and secondary efficacy endpoints will be analyzed for the mITT population 
(Table 9-2). All other efficacy endpoints and analyses will be defined in the SAP. 
Table 9-2 
Primary and Secondary Endpoints 
Endpoint 
Description 
Timing 
Methodology 
C-APPS Responder 
(primary endpoint)  
Achievement of ≥ 1-grade C-APPS 
improvement at maximum contraction 
 
 at Day 14  
Day 14 
Responder 
P-APPS Responder 
(secondary endpoint) 
Achievement of ≥ 1-grade P-APPS 
improvement at maximum contraction
 
 at Day 14 
Day 14 
Responder 
 
9.4.1.2. 
Multiple Comparisons Procedure 
The overall FWER will be controlled at α = 0.05 for the set of primary and secondary endpoint 
comparisons between each of the BOTOX groups versus placebo (4 comparisons). The overall 
serial gatekeeping MCP will be used to control FWER and is defined in Table 9-3. 
Table 9-3 
Multiple Comparisons Procedure 
MCP Stepa 
Endpoint 
MCP Criteria 
1 
C-APPS responder (BOTOX high dose vs placebo) 
Nominal p-value ≤ α 
2 
P-APPS responder (BOTOX high dose vs placebo) 
Nominal p-value ≤ α 
3 
C-APPS responder (BOTOX low dose vs placebo) 
Nominal p-value ≤ α 
4 
P-APPS responder (BOTOX low dose vs placebo) 
Nominal p-value ≤ α 
a 
Serial gatekeeping MCP only proceeds to next step if all endpoints are statistically significant after 
application of MCP criteria in previous and current MCP steps for a BOTOX group.  
 

 
 
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9.4.1.3. 
Primary and Secondary Analyses 
The proportion of responders will be analyzed using CMH tests 
 
. In addition, 2-sided 95% confidence intervals for the treatment differences in response 
rates will be provided. Between group comparisons will only be performed for each BOTOX 
group against the placebo group, and BOTOX high dose group against the BOTOX low dose 
group. 
9.4.2. 
Safety Analyses 
The safety analyses will be performed using the safety population and will be fully defined in the 
SAP. The safety parameters will include AEs and vital signs. For each safety parameter, the last 
nonmissing safety assessment before the first dose of study intervention will be used as the 
baseline for all analyses of that safety parameter. 
9.4.2.1. 
Adverse Events 
An AE will be considered a TEAE if: 
• The AE began after the first dose of study intervention; or 
• The AE was present before the first dose of study intervention, but increased in severity or 
became serious after the first dose of study intervention 
An AE will be considered a serious TEAE if it is a TEAE that additionally meets any SAE 
criteria. 
The total number and percentage of participants reporting AEs, TEAEs, treatment-related 
TEAEs, serious TEAEs, treatment-related serious TEAEs, deaths, and discontinuations due to 
TEAEs will be summarized for each treatment group. 
The number and percentage of participants reporting TEAEs in each study intervention group 
will be tabulated by system organ class, preferred term, and severity. 
The number and percentage of participants reporting serious TEAEs in each study intervention 
group will be tabulated by system organ class and preferred term. 
The number and percentage of participants reporting treatment-related TEAEs in each study 
intervention group will be tabulated by system organ class and preferred term.  
If more than 1 AE is coded to the same PT for the same participant, the participant will be 
counted only once for that preferred term using the most severe and most related occurrence for 
the summarizations by severity and by relationship to study intervention.  
The number and percentage of participants reporting TEAEs that are included in the possible 
distant spread of toxin (PDSOT) term list in each study intervention group will be tabulated by 
preferred term. The PDSOT term list will be provided by the medical safety physician (MSP).  
The PDSOT will be reviewed by the MSP on a monthly basis for monitoring severity, frequency, 
and trending.  

 
 
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10. 
Supporting Documentation and Operational Considerations 
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations 
10.1.1. 
Regulatory and Ethical Considerations 
• This study will be conducted in accordance with the protocol and with the following: 
o Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and CIOMS International Ethical Guidelines 
o Applicable ICH/ISO/GCP guidelines 
o Applicable laws and regulations 
• The protocol, protocol amendments, ICF, IB, and other relevant documents (eg, 
advertisements) must be submitted to an IRB/IEC by the investigator and reviewed and 
approved by the IRB/IEC before the study is initiated. 
• Any amendments to the protocol will require IRB/IEC approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an immediate 
hazard to study participants.  
• The investigator will be responsible for the following: 
o Providing written summaries of the status of the study to the IRB/IEC annually or more 
frequently in accordance with the requirements, policies, and procedures established by 
the IRB/IEC 
o Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures 
o Providing oversight of the overall conduct of the study at the site and adherence to 
requirements of applicable local regulations, for example 21 CFR, ICH guidelines, the 
IRB/IEC, and European regulation 536/2014 for clinical studies (if applicable) 
10.1.2. 
Financial Disclosure 
Investigators and subinvestigators will provide the sponsor with sufficient, accurate financial 
information as requested to allow the sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators are 
responsible for providing information on financial interests during the study and for 1 year after 
completion of the study. 

 
 
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10.1.3. 
Informed Consent Process 
• The investigator or his/her representative will explain the nature of the study to the 
participant and answer all questions regarding the study.  
• Participants must be informed that their participation is voluntary. Participants will be 
required to sign a statement of informed consent that meets the requirements of 21 CFR 50, 
local regulations, ICH guidelines, HIPAA requirements, where applicable, and the IRB/IEC 
or study center.  
• The medical record must include a statement that written informed consent was obtained 
before the participant was enrolled in the study and the date the written consent was obtained. 
The authorized person obtaining the informed consent must also sign the ICF. 
• Participants must be re-consented to the most current version of the ICF(s) during their 
participation in the study.  
• A copy of the ICF(s) must be provided to the participant or the participant’s legally 
authorized representative.  
• Participants who are rescreened are not required to sign a new ICF if rescreening occurs 
within 14 days of first signing the ICF.  
10.1.4. 
Data Protection 
• Participants will be assigned a unique identifier. Any participant records, datasets, or 
photographs that are transferred to the sponsor will contain the identifier only; participant 
names or any information which would make the participant identifiable will not be 
transferred.  
• The participant must be informed that his/her personal study-related data will be used by the 
sponsor in accordance with local data protection law. The level of disclosure must also be 
explained to the participant.  
• The participant must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the sponsor, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities. 
10.1.5. 
Posting Clinical Study Data 
• Company-sponsored study information and tabular study results will be posted to the US 
National Institutes of Health website www.clinicaltrials.gov and other publicly accessible 
sites, if applicable. 
• Study data and information may be published in non-promotional, peer-reviewed 
publications either by or on behalf of the sponsor. 
• Clinical study reports, safety updates and annual reports will be provided to regulatory 
authorities as required. 

 
 
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10.1.6. 
Data Quality Assurance 
• All participant data relating to the study will be recorded on printed or eCRFs unless 
transmitted to the sponsor or designee electronically. The investigator is responsible for 
verifying that data entries are accurate and correct by electronically signing the eCRF.  
• The investigator must maintain accurate documentation (source data) that supports the 
information entered in the eCRF.  
• The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents.  
• The sponsor or designee is responsible for the data management of this study including 
quality checking of the data.  
• Study monitors will perform ongoing source data verification to confirm that data entered 
into the CRF by authorized site personnel are accurate, complete, and verifiable from source 
documents; that the safety and rights of participants are being protected; and that the study is 
being conducted in accordance with the currently approved protocol and any other study 
agreements, ICH GCP, and all applicable regulatory requirements.  
• Records and documents, including signed ICFs, pertaining to the conduct of this study must 
be retained by the investigator as stated in the clinical trial agreement. No records may be 
destroyed during the retention period without the written approval of the sponsor. No records 
may be transferred to another location or party without written notification to the sponsor.  
10.1.7. 
Source Documents 
• Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. Source documents are filed at the investigator’s site. 
• Data entered in the eCRF that are transcribed from source documents must be consistent with 
the source documents or the discrepancies must be explained. The investigator may need to 
request previous medical records or transfer records, depending on the study. Also, current 
medical records must be available. 
• Definition of what constitutes source data can be found in Section 4.0 of ICH E6, Good 
Clinical Practice: Consolidated Guidance and must follow ALCOA, ie, records must be 
attributable, legible, contemporaneous, original, and accurate. 
• Source data are defined as: original documents, data, and records (eg, hospital records, 
clinical and office charts, diaries or evaluation checklists, pharmacy dispensing records, 
recorded data from automated instruments, copies or transcriptions certified after verification 
as being accurate and complete, microfiche, photographic images, negatives, microfilm or 
magnetic media, X-rays, participant files, and records kept at the pharmacy, at the 
laboratories, and at medico-technical departments involved in the clinical study). These 
records include, but are not limited to, original signed and dated consent forms, relevant 

 
 
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observations including records of AEs, and records of all exposure to study intervention, and 
data entered directly into an eCOA device. 
• The following information should be entered into the participant’s source records, including 
but not limited to: 
o Statement that standardized photographs were taken as appropriate and data images 
submitted to the designated third-party vendor 
o Pregnancy test results for WOCBP 
10.1.8. 
Study and Site Closure 
The sponsor designee reserves the right to close the study site or terminate the study at any time 
for any reason at the sole discretion of the sponsor. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study supplies 
have been collected and a study-site closure visit has been performed. 
The investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by the sponsor or investigator may include but are 
not limited to: 
• Failure of the investigator to comply with the protocol, the requirements of the IRB/IEC or 
local health authorities, the sponsor’s procedures, or GCP guidelines 
• Inadequate recruitment of participants by the investigator 
• Discontinuation of further development of study intervention 
10.1.9. 
Publication Policy 
• Allergan as the sponsor has proprietary interest in this study. Authorship and manuscript 
composition will reflect joint cooperation between multiple investigators and sites and 
Allergan personnel. Authorship will be established prior to the writing of the manuscript. As 
this study involves multiple centers, no individual publications will be allowed prior to 
completion of the final report of the multicenter study except as agreed with Allergan.  
• The sponsor will comply with the requirements for publication of study results. In 
accordance with standard editorial and ethical practice, the sponsor will generally support 
publication of multicenter studies only in their entirety and not as individual site data. 
• Authorship will be determined by mutual agreement and in line with International Committee 
of Medical Journal Editors authorship requirements. 
10.1.10. 
Compliance with Protocol 
The investigator is responsible for compliance with the protocol at the investigational site. A 
representative of the sponsor will make frequent contact with the investigator and his/her 
research staff and will conduct regular monitoring visits at the site to review participant and 

 
 
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study intervention accountability records for compliance with the protocol. Protocol deviations 
will be discussed with the investigator upon identification. The use of the data collected for the 
participant will be discussed to determine if the data are to be included in the analysis. The 
investigator will enter data that may be excluded from analysis as defined by the protocol 
deviation specifications. Significant protocol deviations will be reported to the IRB/IEC 
according to the IRB/IEC’s reporting requirements. 

 
 
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10.2. 
Appendix 2: Clinical Laboratory Tests 
Not applicable. 

 
 
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10.4. 
Appendix 4: Abbreviations 
3D 
 
3-dimensional 
AE 
 
adverse event 
  
 
ALCOA 
attributable, legible, contemporaneous, original, and accurate 
 
 
 
 
 
BOTOX 
botulinum toxin type A purified neurotoxin 
BP 
 
blood pressure 
C-APPS 
Clinician Allergan Platysma Prominence Scale 
CDISC 
Clinical Data Interchange Standards Consortium 
CFR 
 
code of federal regulations 
CIOMS 
Council for International Organizations of Medical Sciences 
CMH  
Cochran-Mantel-Haenszel 
CONSORT 
Consolidated Standards of Reporting Trials 
CRO  
contract research organization 
eCOA  
electronic clinical outcomes assessment (via tablet) 
eCRF  
electronic case report form 
EDC  
electronic data capture 
EOS 
 
end of study 
FWER  
familywise error rate 
GCP 
 
good clinical practice 
HEENT 
head, eyes, ears, nose, throat 
HIPAA 
Health Insurance Portability and Accountability Act of 1996 
IB 
 
investigator’s brochure 
ICF 
 
informed consent form 
ICH 
 
International Council on Harmonisation 
IDR 
 
independent drug reconstitutor 
IEC 
 
independent ethics committee 
IND 
 
Investigational New Drug 

 
 
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IRB 
 
institutional review board 
ISO 
 
International Organization for Standardization 
IWRS  
Interactive Web Response System 
MCP  
multiple comparisons procedure 
mITT  
modified intent-to-treat 
MSP  
medical safety physician 
NCI 
 
National Cancer Institute 
P-APPS  
Participant Allergan Platysma Prominence Scale 
PDSOT 
possible distant spread of toxin 
  
 
  
 
  
 
 
 
PRO 
 
patient reported outcome 
PT 
 
preferred term 
SAE 
 
serious adverse event 
SAP 
 
statistical analysis plan 
SoA 
 
Schedule of Activities 
SUSAR 
suspected unexpected serious adverse reactions 
TEAE  
treatment-emergent adverse event 
WOCBP 
woman of childbearing potential 
 

 
 
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10.5. 
Appendix 5: Standard Discontinuation Criteria 
This table provides participant discontinuation criteria for this protocol. CDISC terminology is 
used, and thus subject or patient is used instead of participant (as used elsewhere in this 
protocol). These terms are interchangeable. 
CDISC Submission Value 
CDISC Definition 
Adverse event 
Any untoward medical occurrence in a patient or 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 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. 
For further information, see the ICH Guideline for Clinical Safety 
Data Management: Definitions and Standards for Expedited 
Reporting (modified from ICH E2A) Synonyms: side effect, 
adverse experience. See also serious adverse event, serious adverse 
experience. (CDISC glossary) 
Completed 
To possess every necessary or normal part or component or step; 
having come or been brought to a conclusion (NCI) 
Death 
The absence of life or state of being dead (NCI) 
Lost to follow-up 
The loss or lack of continuation of a subject to follow-up 
Other 
Different than the one(s) previously specified or mentioned (NCI) 
Physician decision 
A position, opinion or judgment reached after consideration by a 
physician with reference to subject (NCI) 
Pregnancy 
Pregnancy is the state or condition of having a developing embryo 
or fetus in the body (uterus), after union of an ovum and 
spermatozoon, during the period from conception to birth. (NCI) 
Protocol deviation 
An event or decision that stands in contrast to the guidelines set out 
by the protocol (NCI) 
Screen failure 
The potential subject who does not meet one or more criteria 
required for participation in a trial 
Site terminated by sponsor 
An indication that a clinical study was stopped at a particular site 
by its sponsor (NCI) 
Study terminated by sponsor 
An indication that a clinical study was stopped by its sponsor (NCI) 
Withdrawal by subject 
An indication that a study participant has removed itself from the 
study (NCI) 

 
 
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10.6. 
Appendix 6: Study Tabular Summary 
This table is intended for use in posting study information to registries (eg, ClinicalTrials.gov). 
Parameter Group 
Parameter 
Value 
Trial information 
Trial Title 
A Phase 2 Multicenter, Randomized, 
Double-Blind, Placebo-Controlled, Dose-
Ranging Study to Evaluate the Safety and 
Efficacy of BOTOX® (Botulinum Toxin 
Type A) Purified Neurotoxin Complex for 
the Treatment of Platysma Prominence 
 
Clinical Study Sponsor 
Allergan Sales LLC 
 
Trial Phase Classification 
Phase 2  
 
Trial Indication 
Platysma Prominence 
 
Trial Indication Type 
Treatment 
 
Trial Type 
Efficacy 
Safety 
 
Trial Length 
Approximately 4 months 
 
Planned Country of Investigational Sites 
United States and Canada 
 
Planned Number of Subjects 
165 
 
FDA-Regulated Device Study 
No 
 
FDA-Regulated Drug Study 
Yes 
 
Pediatric Study 
No 
Subject information 
Diagnosis Group 
Adults with moderate to severe platysma 
prominence  
 
Healthy Subject Indicator 
Yes 
 
Planned Minimum Age of Subjects 
18 
 
Planned Maximum Age of Subjects 
No upper age limit 
 
Sex of Participants 
Male or Female 
 
Stable Disease Minimum Duration 
Not applicable  

 
 
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Parameter Group 
Parameter 
Value 
Treatments 
Investigational Therapy or Treatment 
OnabotulinumtoxinA 
 
Intervention Type 
Drug 
 
Pharmacological Class of Invest. Therapy 
Neurotoxin 
 
Dose per Administration 
Up to 
 U 
 
Dose Units 
U 
 
Dosing Frequency 
Single-treatment on Day 1  
 
Route of Administration 
Intramuscular 
 
Current Therapy or Treatment 
Not applicable 
 
Added on to Existing Treatments 
No 
 
Control Type 
Placebo 
 
Comparative Treatment Name 
Not applicable 
Trial design 
Study Type 
Interventional 
 
Intervention Model 
Parallel 
 
Planned Number of Arms 
3 
 
Trial is Randomized 
Yes 
 
Randomization Quotient 
1:1:1 (BOTOX high dose:BOTOX low 
dose:placebo) 
 
Trial Blinding Schema 
Double blind 
 
 
 
 
Adaptive Design 
No 
 
Study Stop Rules 
Not applicable  
 

 
 
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10.7. 
Appendix 7: Contraceptive Guidance and Collection of Pregnancy 
Information 
Definitions: 
Woman of Childbearing Potential (WOCBP) 
A woman is considered fertile following menarche and until becoming postmenopausal unless 
permanently sterile (see below). 
Women in the following categories are not considered WOCBP: 
1. Premenarchal 
2. Premenopausal female with 1 of the following: 
• Documented hysterectomy 
• Documented bilateral salpingectomy 
• Documented bilateral oophorectomy 
Note: Documentation can come from the site personnel’s: review of the participant’s 
medical records, medical examination, or medical history interview. 
3. Postmenopausal female 
• A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. A high follicle-stimulating hormone (FSH) level in the postmenopausal 
range may be used to confirm a postmenopausal state in women not using hormonal 
contraception or hormonal replacement therapy (HRT). However, in the absence of 
12 months of amenorrhea, a single FSH measurement is insufficient.  
Contraception Guidance: 
Female Participants 
Female participants of childbearing potential are eligible to participate if they agree to use a 
highly effective method or acceptable method of contraception consistently and correctly as 
described in Table 10–1. 

 
 
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Table 10–1 
Highly Effective and Acceptable Contraceptive Methods 
Highly Effective Contraceptive Methods That Are User Dependenta  
Failure rate of < 1% per year when used consistently and correctly  
Combined (estrogen- and progestogen-containing) hormonal contraception associated with inhibition of 
ovulationb  
• 
Oral  
• 
Intravaginal  
• 
Transdermal  
Progestogen-only hormonal contraception associated with inhibition of ovulation 
• 
Oral  
• 
Injectable  
Highly Effective Methods That Are User Independenta  
Implantable progestogen-only hormonal contraception associated with inhibition of ovulation 
• 
Intrauterine device (IUD) 
• 
Intrauterine hormone-releasing system (IUS) 
• 
Etonogestrel implant (ie, Nexplanon®) 
Bilateral tubal occlusion 
Intrauterine copper contraceptive (ie, ParaGard®) 
Vasectomized Partner  
A vasectomized partner is a highly effective contraception method provided that the partner is the sole male 
sexual partner of the WOCBP and the absence of sperm has been confirmed. If not, an additional highly effective 
method of contraception should be used.  
Sexual Abstinence  
Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual 
intercourse during the entire period of risk associated with the study intervention. The reliability of sexual 
abstinence needs to be evaluated in relation to the duration of the study and the preferred and usual lifestyle of 
the participant.  
Acceptable Methods  
Acceptable birth control methods that result in a failure of more than 1% per year include: 
• 
Progestogen-only oral hormonal contraception, where inhibition of ovulation is not the primary mode of 
action 
• 
Male or female condom with or without spermicide  
• 
Cap, diaphragm, or sponge with spermicide 
• 
Nonhormonal intrauterine device  
A combination of male condom with either cap, diaphragm, or sponge with spermicide (double-barrier methods) 
are also considered acceptable, but not highly effective, birth control methods. 
a Typical use failure rates may differ from those when used consistently and correctly. Use should be consistent 
with local regulations regarding the use of contraceptive methods for participants participating in clinical 
studies.  
 

 
 
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Pregnancy Testing: 
• 
WOCBP should only be included after a confirmed menstrual period and a negative highly 
sensitive pregnancy test at screening and also a negative test on Day 1. 
• 
Additional pregnancy testing may also be performed at any other study visit at the 
investigator’s discretion and at the study exit visit, and as required locally. 
• 
Pregnancy testing will be performed whenever a menstrual cycle is missed or when 
pregnancy is otherwise suspected.  
Collection of Pregnancy Information: 
Female Participants Who Become Pregnant  
• 
The investigator will collect pregnancy information on any female participant who becomes 
pregnant while participating in this study. Information will be recorded on the appropriate 
form and submitted to the sponsor within 24 hours of learning of a participant’s pregnancy. 
The participant will be followed to determine the outcome of the pregnancy. The 
investigator will collect follow-up information on the participant and the neonate, and the 
information will be forwarded to the sponsor. Generally, follow-up will not be required for 
longer than 6 to 8 weeks beyond the estimated delivery date. Any termination of pregnancy 
will be reported, regardless of fetal status (presence or absence of anomalies) or indication 
for the procedure. 
• 
While pregnancy itself is not considered to be an AE or SAE, any pregnancy complication 
will be reported as an AE or SAE. A spontaneous or elective abortion is always considered 
to be an SAE and will be reported as such. Any poststudy pregnancy-related SAE 
considered reasonably related to the study intervention by the investigator will be reported to 
the sponsor as described in Section 8.3.4. While the investigator is not obligated to actively 
seek this information in former study participants, he or she may learn of an SAE through 
spontaneous reporting.  
• 
If a pregnancy is confirmed after the participant has received study intervention, the 
participant may choose to exit the study after appropriate safety follow-up or to remain in the 
study for all safety and efficacy follow-up assessments through the end-of-study visit. 

 
 
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10.8. 
Appendix 8: Clinician Allergan Platysma Prominence Scale 
C-APPS grades and descriptions are shown in Section 8.1.1, Table 8-1. 

 
 
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10.9. 
 
 

 
 
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10.10. 
Appendix 10: Example Patient-Reported Outcomes Questionnaires, 
Descriptions, and Instructions 
This appendix provides complete samples of each questionnaire; however, participants will 
provide responses in electronic tablets (ie, eCOA) at the site. 

 
 
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BOTOX 
 
DENTIAL 
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DENTIAL 
83 
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10.11. 
Fitzpatrick Skin Phototype 
 
Type 
Description 
I 
Always burns easily; never tans (sensitive) 
II 
Always burns easily; tans minimally (sensitive) 
III 
Burns moderately; tans gradually (light brown) (normal) 
IV 
Burns minimally; always tans well (moderate brown) (normal) 
V 
Rarely burns; tans profusely (dark brown) (insensitive) 
VI 
Never burns; deeply pigmented (insensitive) 
Source: Federal Register 1999 
 

 
 
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References 

 
 
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