Prospective, Evaluator-blind, Multicenter Study to Assess the Safety and Effectiveness of Treatment With the Octave System for Improving Lines and Wrinkles of the décolleté
Phase: NA
Conditions: Décolleté Wrinkles
Sponsor: Merz North America, Inc.



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comparison will be made at 180 days post-treatment for the secondary 
endpoint. To reduce potential bias associated with evaluating only treated-
subject photographs, images of untreated individuals, collected at two time 
points, will also be included for blinded, independent photographic review. 
Study subjects will have approximately 4 in-office study visits, including 
screening, baseline/treatment, a Day 90 (± 7 days) post-treatment visit, and a 
Day 180 (± 14 days) post-treatment visit. Follow-up telephone calls will 
occur at 3 days (± 1 day), 14 days (± 3 days), 28 days (+ 3 days), 120 days 
(± 7 days), and 150 days (± 7 days) after Octave-Ultherapy treatment. 
Expected study duration is approximately 8 months from screening of the 
first subject until final follow-up of the last subject. In Stage 1, an initial 
cohort of 10 subjects will be enrolled, safety data will be assessed up to 
Week 2, and subjects will participate until the Stage 1 study end at Day 90. 
In Stage 2, all enrolled subjects will participate until study end at Day 90 or 
Day 180 if reconsented for extended participation. The planned duration of 
participation for individual subjects is up to 30 weeks, including up to 
21 days for screening, 1 day for treatment, and 90 or 180 days for follow-up. 
Number of 
Study Subjects 
Approximately 113 subjects are planned for screening to allow for 
90 enrolled/treated subjects and 80 evaluable subjects in this study. In 
Stage 1, 10 subjects will be enrolled, while all other subjects will be enrolled 
in Stage 2. 
Main Inclusion/ 
Exclusion 
Criteria 
Key inclusion criteria are as follows: 
−
Healthy female aged 35 to 65 years at the time of screening.
−
Moderate to severe fine lines, wrinkles, laxity, and crepiness of the
décolleté that is amenable to improvement with non-invasive
intervention and is not severe enough for surgical intervention.
Key exclusion criteria are as follows: 
−
Presence of an active systemic or local skin disease that may affect
wound healing.
−
Scarring in area(s) to be treated.
−
Active implants (e.g., pacemakers or defibrillators), ports, or metallic
implants in area(s) to be treated.
−
Breast implants or is planning to receive breast implants during the
study.
−
Inability to take pre-treatment medications due to a pre-existing
condition, medication allergy, or medical issue that, at the discretion of
the treating investigator, is contraindicated.

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3 TABLE OF CONTENTS 
1 
TITLE PAGE ...................................................................................................... 1 
2 
SYNOPSIS ............................................................................................................ i 
3 
TABLE OF CONTENTS..................................................................................... 6 
4 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ..................... 10 
5 
ETHICS ............................................................................................................. 12 
5.1 
Ethical Conduct of the Study ............................................................................ 12 
5.2 
Informed Consent ............................................................................................ 12 
5.3 
Subject Privacy ................................................................................................ 13 
5.4 
Confidentiality of Subject Information .............................................................. 13 
6 
INTRODUCTION ............................................................................................. 14 
6.1 
Background ..................................................................................................... 14 
6.2 
Study Rationale................................................................................................ 18 
6.3 
Potential Benefits and Risks ............................................................................. 19 
7 
STUDY OBJECTIVE AND ENDPOINTS ........................................................ 21 
7.1 
Objective ......................................................................................................... 21 
7.2 
Endpoints ........................................................................................................ 21 
7.2.1 
Effectiveness Endpoints.............................................................................. 21 
7.2.1.1 
Primary Effectiveness Endpoint............................................................ 21 
7.2.1.2 
Secondary Effectiveness Endpoint ........................................................ 21 
7.2.2 
Safety Endpoints ........................................................................................ 22 
7.2.2.1 
Secondary Safety Endpoint ................................................................... 22 
8 
CLINICAL INVESTIGATION PLAN.............................................................. 24 
8.1 
Overview of Study Design................................................................................ 24 
8.2 
Discussion of Study Design, Including the Choice of Control Groups ................ 25 
9 
STUDY POPULATION AND RESTRICTIONS .............................................. 26 
9.1 
Number of Subjects and Sites ........................................................................... 26 
9.2 
Selection of Subject Population ........................................................................ 26 
9.2.1 
Inclusion Criteria........................................................................................ 27 
9.2.2 
Exclusion Criteria ...................................................................................... 28 
9.2.4 
Subject Enrollment ..................................................................................... 31 
9.2.5 
Screen Failures........................................................................................... 31 
9.2.6 
Removal of Subjects from Therapy or Assessment ...................................... 32 
9.2.6.1 
Treatment Discontinuation ................................................................... 32 

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9.2.6.2 
Subject Withdrawal or Discontinuation ................................................ 32 
9.2.6.3 
Provision of Care for Subjects after Study Discontinuation ................... 33 
9.2.7 
Suspension or Premature Termination of a Study Site .................................. 33 
9.2.8 
Suspension or Premature Termination of the Study...................................... 34 
9.2.9 
Subject Completion .................................................................................... 35 
9.2.10 
End of Study .............................................................................................. 35 
10 STUDY DEVICE AND TREATMENT OF SUBJECTS................................... 36 
10.1 
Description of Study Device ............................................................................. 36 
10.1.1 
Mechanism of Action ................................................................................. 37 
10.1.2 
Operating Information ................................................................................ 37 
10.2 
Instructions for Use and Administration ............................................................ 39 
10.3 
Methods of Assigning Subjects to Treatment Groups ........................................ 39 
10.4 
Blinding Procedures ......................................................................................... 40 
10.5 
Study Treatment............................................................................................... 40 
10.5.1 
Planned Treatment Procedure and Administration ....................................... 40 
10.5.1.1 
Pre-Treatment Assessments .................................................................. 40 
10.5.1.2 
Pre-Treatment Medications and Procedure .......................................... 40 
10.5.1.3 
Treatment Region and Administration Procedure.................................. 42 
10.5.2 
Selection and Timing of Treatment for Each Subject ................................... 44 
10.5.3 
Treatment Interruption and Modification..................................................... 44 
10.6 
Prior and Concomitant Therapy ........................................................................ 44 
10.7 
Study Supplies and Packaging of Treatment Supplies ........................................ 45 
10.8 
Receipt, Storage, Dispensing, and Return/Disposal ........................................... 45 
10.9 
Device Accountability Procedures .................................................................... 45 
10.10 Treatment Compliance ..................................................................................... 46 
10.11 Duration of Study............................................................................................. 46 
11 STUDY PROCEDURES.................................................................................... 47 
11.1 
Visit Schedule.................................................................................................. 47 
11.1.1 
Scheduled Visits......................................................................................... 48 
11.1.2 
Unscheduled Visits..................................................................................... 48 
11.2 
Study Assessments and Definitions................................................................... 49 
11.2.1 
Effectiveness Assessments.......................................................................... 49 
11.2.1.1 
Standardized 2D Photographs.............................................................. 49 
11.2.2 
Safety Assessments .................................................................................... 52 
11.2.2.1 
Adverse Events (AEs)/Serious Adverse Events (SAEs) ........................... 52 
11.2.3 
Additional Data Collected........................................................................... 54 
12 SAFETY DEFINITIONS AND REPORTING REQUIREMENTS .................. 56 
12.1 
Definition of an Adverse Event (AE) ................................................................ 56 
12.1.1 
Details of an AE ......................................................................................... 56 

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12.1.2 
Reporting and Handling of an AE ............................................................... 56 
12.1.3 
Severity Grading for an AE ........................................................................ 57 
12.1.4 
Causal Relationship of an AE with an Investigational Medical Device ......... 57 
12.1.5 
Outcome Categories for an AE ................................................................... 58 
12.2 
Definition of a Serious Adverse Event (SAE).................................................... 58 
12.2.1 
Details of an SAE....................................................................................... 59 
12.2.2 
Reporting and Handling of an SAE ............................................................. 59 
12.3 
Definition of an Adverse Device Effect (ADE) ................................................. 60 
12.4 
Definition of a Serious Adverse Device Effect (SADE) ..................................... 61 
12.4.1 
Definition of an Anticipated Serious Adverse Device Effect (ASADE) ........ 61 
12.4.2 
Definition of an Unanticipated Adverse Device Effect (UADE) ................... 61 
12.5 
Definition of Device Deficiency ....................................................................... 61 
12.6 
Definition of Technical Complaint.................................................................... 61 
12.6.1 
Reporting and Handling of Device Deficiencies .......................................... 62 
12.8 
Reporting of Pregnancy .................................................................................... 63 
13 STATISTICAL METHODS .............................................................................. 64 
13.1 
Estimation of Sample Size................................................................................ 64 
13.2 
Randomization................................................................................................. 64 
13.3 
Populations for Analysis................................................................................... 64 
13.4 
Analysis of Study Data..................................................................................... 65 
13.4.1 
Effectiveness Analyses ............................................................................... 65 
13.4.1.1 
Primary Effectiveness Endpoint............................................................ 65 
13.4.1.2 
Secondary Effectiveness Endpoint ........................................................ 66 
13.4.2 
Safety Analyses.......................................................................................... 66 
13.4.2.1 
Secondary Safety Endpoint ................................................................... 67 
13.4.3 
Other Subject Data ..................................................................................... 68 
13.5 
Special Statistical/Analytical Issues .................................................................. 69 
13.5.1 
Subject Discontinuation and Missing Data .................................................. 69 
13.5.2 
Interim Analysis ......................................................................................... 69 
14 ADMINISTRATIVE PROCEDURES............................................................... 70 
14.1 
Study Monitoring ............................................................................................. 70 
14.2 
Data Quality Assurance .................................................................................... 70 
14.2.1 
Standardization Procedures......................................................................... 70 
14.2.2 
Data Management ...................................................................................... 70 
14.2.3 
Data Review and Clarification Procedures................................................... 71 
14.2.4 
Auditing..................................................................................................... 72 
14.3 
Record Retention ............................................................................................. 72 
14.4 
Publication Policy ............................................................................................ 73 
14.5 
Financial Disclosure......................................................................................... 74 
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14.6 
Investigator Compliance................................................................................... 74 
15 REFERENCES .................................................................................................. 75 
16 APPENDICES ................................................................................................... 77 

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5 ETHICS 
5.1 
Ethical Conduct of the Study 
This study will be performed in accordance with the principles outlined in the Declaration 
of Helsinki and in compliance with the International Council for Harmonisation of 
Technical Requirements for Pharmaceuticals for Human Use’s Good Clinical Practice 
(ICH-GCP), EN ISO 14155, the Code of Federal Regulations (CFR), and any applicable 
regional or national laws and regulations. The study will adhere to all applicable subject 
privacy requirements. 
All required approvals, favorable opinions, or additional requirements of the appropriate 
Independent Ethics Committee (IEC), Institutional Review Board (IRB), or other 
regulatory authority will be obtained prior to initiation of the trial. 
The investigator and all study personnel will conduct the study in compliance with this 
protocol. The investigator will ensure all personnel involved in the conduct of this study 
are qualified to perform the assigned study responsibilities. Investigators will adhere to all 
applicable study reporting requirements. 
5.2 
Informed Consent 
Verbal and written informed consent must be obtained from every subject prior to the 
initiation of any screening or study procedures. The investigator will follow a standard 
process for obtaining consent that complies with all applicable regulatory requirements. 
If applicable, a certified, local-language translation of the informed consent form (ICF) 
will be provided. 
If the ICF is amended during the study, the investigator must follow all applicable 
regulatory requirements pertaining to approval of the amended ICF by the IEC/IRB and 
use of the amended form. Ongoing subjects will be required to re-confirm consent by 
signing the amended form. 
The original and any amended signed and dated ICF(s) must be retained at the study site; 
a copy of the signed and dated ICF(s) must be given to the subject. 
During the study, the subject will be informed if information becomes available that may 
be relevant to the subject’s willingness to continue participation in the study. Each ICF will 
include contact information (with a phone number) the subject should use to communicate 
any medical concerns 24 hours a day. The subject, however, is free to withdraw consent at 
any time and for any reason, whether expressed or not. 

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5.3 
Subject Privacy 
The subject will be informed of procedures to protect subject privacy. Under US federal 
law (the Privacy Rule), any protected health information (PHI) that is created or obtained 
during this study cannot be used or disclosed without permission. The currently designated 
statistical contract research organization (CRO) processes subject data in accordance with 
the data-protection provisions set forth in the German Federal Data Protection Act 
(Bundesdatenschutzgesetz), specifically in the version applicable as of 25-MAY-2018, and 
in 
the 
European-focused 
General 
Data Protection 
Regulation 
law 
(GDPR). 
Informed consent on data processing will be obtained in writing directly from the subject 
before recording of any data. Authorization to use and disclose PHI will be obtained in 
writing directly from the subject before recording of any data. Recorded data will be 
pseudonymized before transferring to authorized individuals. The investigator will 
maintain source documents linking unique subject numbers with subject names (e.g., in 
case of emergencies). 
At the conclusion of the study, subject photographs will be stored and archived 
electronically by the sponsor and the study site. Photographs allowing identification of the 
subject will be published only if the subject has given written permission. 
5.4 
Confidentiality of Subject Information 
Subject pseudoanonymity is to be maintained during the study. Subjects will be identified 
by a unique subject number on all study documentation. Health information that could 
identify the subject (i.e., PHI) must be maintained in strict confidence by the investigator 
to the extent permitted by applicable laws and regulations. Subjects must sign an 
authorization to allow PHI to be disclosed to the sponsor and anyone working on behalf of 
the sponsor, the IRB/IEC, or regulatory authorities. 
Confidentiality will also be maintained for any medical information obtained from the 
subject during study participation. At a subject’s request, the subject’s medical information 
may be provided to the subject’s personal physician or other appropriate medical personnel. 
If the results of the investigation are published, the subject’s identity will remain 
confidential. 

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6 INTRODUCTION 
6.1 
Background 
Many factors contribute to the natural aging process during which an individual’s skin 
gradually loses its youthful appearance. Aging skin is characterized by loss of volume, 
decreased elasticity, and increased laxity. Various aesthetic techniques have been used in 
an attempt to reverse or slow the aging process. As such, individuals are increasingly 
undergoing facial rejuvenation procedures; after treatment, they often notice the improved 
appearance of the face is in contrast with that of the untreated aging neck and chest. The 
chest and neck are exposed to substantial ultraviolet (UV) radiation and both regions tend 
to demonstrate photoaging. Additionally, the chest skin of females is vulnerable to the 
mechanical stress of the weight and movement of the breasts.[1] Aging of the skin in the 
décolleté region manifests as atrophy, laxity, wrinkles, and dyspigmentation. 
Special anatomic considerations exist when treating the skin of the décolleté. The skin in 
this area is thinner than some areas of the face[2] as well as the arms and legs.[1] 
Additionally, there are over 13 times fewer hair follicles on the chest than on the lateral 
forehead.[3] This difference in pilosebaceous units contributes to the slower healing and 
increased risk of scarring with aesthetic treatments of the décolleté region, particularly 
ablative ones.[4] Modalities used to treat signs of aging in the décolleté region include 
neurotoxins, fillers, chemical peels, intense pulsed light, and non-ablative and ablative 
lasers.[5] 
Various energy-delivery devices, designed to create thermal injury to stimulate fibroblast 
synthesis and collagen production (e.g., fractionated ablative lasers, radiofrequency 
devices, fractional infrared devices), have been developed.[6] While these energy-based 
devices have demonstrated tightening effects on superficial layers of the skin, ultrasound 
energy can cause deeper skin-tightening effects by delivering focused energy to the dermis. 
Furthermore, ultrasound-energy use is associated with fewer adverse post-treatment effects 
when compared to epidermal treatments, due to its penetration of the deeper layers of skin 
while leaving the epidermal layers and intervening skin tissues unaffected.[7] This 
characteristic of microfocused ultrasound is particularly beneficial in patients of higher 
Fitzpatrick skin types (FST III to VI)[8], as melanocytes and melanin are superficial to the 
treatment location. As a result, microfocused ultrasound tends not to affect skin pigment 
and is safe for use in all FST.[9] 
The Ulthera System is a non-invasive, dermatological, aesthetic treatment that is FDA 
cleared to lift the eyebrow (K072505), lift (K121700) and improve the appearance 
(K180623) of lax submental and neck tissue, and reduce wrinkles and lines in the décolleté 
(K134032). In previous clinical trials, the Ulthera System has demonstrated safety and 
effectiveness as a non-invasive aesthetic treatment. Ultherapy utilizes microfocused 
ultrasound energy with visualization (MFU-V) to create thermal coagulation points (TCPs) 

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6.2 
Study Rationale 
The current confirmatory study is designed to demonstrate the safety and effectiveness of 
the Octave System for improving lines and wrinkles of the décolleté. Analogous to the face 
and neck, changes in décolleté-skin tone and texture, including lines and wrinkles, occur 
with age, creating a concern for many individuals. Additionally, the chest skin of females 
is vulnerable to the mechanical stress of the weight and movement of the breasts, which 
can cause dynamic changes in the skin.[1] Ultherapy targets lines and wrinkles of the 
décolleté and offers a non-invasive approach to improving the aesthetic appearance of this 
region. Subjects with moderate to severe fine lines, wrinkles, laxity, and crepiness of the 
décolleté that is amenable to improvement with non-invasive intervention and is not severe 
enough for surgical intervention will be treated. Subjects will receive one Octave-
Ultherapy treatment of the décolleté tissue and will be followed for 90 or 180 days. 
Previous studies have shown improvement in the aesthetic appearance of the décolleté 
region after DeepSEE Ultherapy treatment as early as 90-days post-treatment
; thus, subjects will be followed 
for the same length of time for the primary endpoint. Subjects will be treated with two 

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because these AEs are reported voluntarily from a population of uncertain size, it is not 
always possible to reliably estimate their frequency or establish a causal relationship with 
the Ulthera DeepSEE System. 
In clinical trials with the first-generation Ulthera DeepSEE system, no device- or 
procedure-related serious adverse events (SAEs) were observed, and reported adverse 
events (AEs) were generally expected, mild in nature, and short in duration.[7, 15-17] 
Long-term follow-up studies confirmed the favorable safety profile of the Ulthera 
DeepSEE system with primarily mild, treatment-related side effects.[10] 
Risks of Ultherapy on the second-generation Octave System will be minimized or reduced 
by training the investigational sites and monitoring the subject during the treatment 
procedure, with careful observation of the subject’s pain and skin response to treatment. 
Previous clinical studies with the Ulthera DeepSEE System have shown the sensory 
response was tolerable from both the subject’s and investigator’s perspective.[10] 
Discomfort was transient, and acute pain resolved within 30 minutes. If the subject is 
uncomfortable during Octave System treatment, the treating investigator has the option to 
utilize additional measures to improve tolerability, including additional/different pain 
medication 
(e.g., see Section 10.5.1.2). If treatment remains intolerable 
after 
implementation of mitigation measures, the investigator or delegated study clinician must 
stop administering treatment, for the subject’s safety, and the subject will be followed for 
AEs throughout the study’s duration. In the case of an AE report, the subject will be 
followed until the subject’s last study visit, until the AE is resolved or stabilized, the subject 
is lost to follow-up, or some other resolution of the event occurs. 
Considering all risks and benefits of Ultherapy on the Octave System, the potential benefits 
to physicians and subjects seeking treatment outweigh the potential risks. The benefit/risk 
ratio of the device is considered acceptable when used on subjects seeking improvement 
of lines and wrinkles of the décolleté. 
Additional information on device- and procedure-related contraindications, warnings, and 
precautions can be found in the current version of the Octave System IFU 
 
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7 STUDY OBJECTIVE AND ENDPOINTS 
7.1 
Objective 
The objective of this study is to demonstrate the safety and effectiveness of the Octave 
System for improving lines and wrinkles of the décolleté. 
7.2 
Endpoints 
7.2.1 
Effectiveness Endpoints 
7.2.1.1 
Primary Effectiveness Endpoint 
• Proportion of treated subjects with improvement in lines and wrinkles of the décolleté 
by comparing photographs taken at Day 90 (post-treatment) with baseline (pre-
treatment) photographs. 
o 
Improvement is concluded if at least two of three independent, blinded 
evaluators assess the Day 90 standardized, photographic images as improved 
compared to baseline photographic images. 
o 
The success criterion is defined by achieving simultaneously a point estimate 
≥ 65% and a lower bound of the one-sided 95% Wilson confidence interval 
> 50% for the proportion of treated subjects with improvement. 
7.2.1.2 
Secondary Effectiveness Endpoint 
• Proportion of treated subjects with improvement in lines and wrinkles of the décolleté 
by comparing photographs taken at Day 180 (post-treatment) with baseline (pre-
treatment) photographs. 
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7.2.2 
Safety Endpoints 
7.2.2.1 
Secondary Safety Endpoint 
• Incidence of treatment-emergent adverse events (TEAEs) related to Octave-Ultherapy 
treatment, as reported throughout the study. 
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9 STUDY POPULATION AND RESTRICTIONS 
9.1 
Number of Subjects and Sites 
Approximately 80 evaluable subjects, who complete the full Ultherapy treatment session 
using the Octave System, are planned for this study. Assuming a screen failure rate of 20%, 
approximately 
113 subjects will be screened; assuming attrition 
of 10 subjects, 
approximately 90 subjects are planned for enrollment/treatment. All subjects will sign and 
date the ICF before any study-related procedures are undertaken. 
In Stage 1, 10 subjects will be enrolled at a minimum of two investigational sites 
(maximum: 6 sites) in the United States, while all other subjects will be enrolled in Stage 2. 
Number of investigational sites will not exceed ten in total. During Stage 1, Week 2 safety 
data for the first 10 treated subjects will be evaluated. All 10 subjects enrolled in Stage 1 
will participate until Stage 1 study end at Day 90. In Stage 2, all other enrolled subjects 
will participate for at least 90 days (± 7 days), with a maximum duration of 180 days 
(± 14 days) if reconsented for extended participation. Females of all FST are eligible for 
study participation. In addition, approximately 10% of the enrolled subjects will be 
categorized as FST IV, V, or VI, and of which 5% will be categorized as FST V or VI. 
Subjects who are enrolled and who do not complete the study will not be replaced. 
Furthermore, the secondary effectiveness endpoin
at Day 180 will 
only be assessed among subjects who reconsent at their Day 90 visit for extended study 
participation to Day 180. 
Photographs of approximately 30 untreated individuals, who meet selected appearance 
criteria (Section 11.2.1.1.1), will be collected at two different time points, between 1 day 
and 1 week apart; these photographs will be subsequently paired for evaluation by the 
independent, blinded evaluators. 
To confirm the presence of appropriate anatomy at the intended depth of treatment (see 
Inclusion Criterion #3 in Section 9.2.1), the treating investigator will use the Octave 
System’s supplemental imaging mode to visualize the dermal and subdermal layers of 
tissue. For example, subjects with bone, rather than soft tissue, at the intended treatment 
depth would be considered screen failures and would not be eligible for enrollment.[16] 
Additional information regarding subject enrollment is provided within the sample size 
justification (Section 13.1). 
9.2 
Selection of Subject Population 
The selection criteria have been chosen to identify a suitable population of subjects to 
investigate the study objectives and to minimize safety concerns in this population. 

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9.2.4 
Subject Enrollment 
Subjects are considered to be enrolled when they provide informed consent (i.e., sign the 
ICF), meet all eligibility criteria, or are treated. 
Screen failures are defined in Section 9.2.5. 
9.2.5 
Screen Failures 
Subjects who provide informed consent but who do not meet eligibility criteria or who 
withdraw consent prior to being treated at the baseline visit will be defined as screen 
failures. The investigator will maintain all source documentation for all subjects who are 
considered screen failures. Minimal information will be collected in the electronic data 
capture (EDC) system for screen failures, such as date of informed consent, demographics, 
and reason for screen failure. In cases when a subject is not meeting eligibility criteria due 

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to a temporary condition, this subject may be rescreened, at the discretion of the treating 
investigator, upon resolution of the temporary condition. 
9.2.6 
Removal of Subjects from Therapy or Assessment 
9.2.6.1 
Treatment Discontinuation 
If study treatment is discontinued during administration, the investigator will record the 
reason for treatment discontinuation 
in the study records. Potential reasons for 
discontinuation of treatment may include refusal by the subject to receive additional 
treatment or physician’s decision. The investigator should request that a subject 
discontinuing treatment continue to participate in the study and complete all remaining 
visits and safety follow-up assessments. For subjects declining continued study 
participation after treatment discontinuation, additional information regarding subject 
withdrawal is provided in Section 9.2.6.2. 
If the subject experiences escalating pain during the Ultherapy procedure that is not 
adequately controlled with the initially selected treatment regimen, the investigators may 
use their discretion to utilize 
further protocol-specific 
options to control pain 
(Section 10.5.1.2). Attempts should be made to optimize pain medication so that treatment 
can be completed. 
9.2.6.2 
Subject Withdrawal or Discontinuation 
Each subject will be followed to the end of study, or until the sponsor decides to terminate 
the study, whichever comes first. The only reasons a subject will not be followed for all 
scheduled visits include withdrawal of consent, continuous non-compliance with protocol 
requirements, or loss to follow-up (e.g., moving away from study site; unresponsive to 
attempts to contact the subject). Additionally, the investigator can discontinue any subject, 
at any time, if medically necessary. 
Subjects have the right to withdraw from the study at any time at their own request without 
prejudice. In cases of withdrawn consent, data collected until the date consent was 
withdrawn will be analyzed as recorded. 
If a subject does not attend a required study visit, the following actions will be taken: 
• The site will attempt to contact the subject at least twice and reschedule the missed visit 
as soon as possible. Every effort to regain contact with the subject will be made 
(e.g., telephone contact on different dates/times, registered mail). All contact attempts 
will be documented. 
• If attempts to contact the subject are not successful, the subject will be considered lost 
to follow-up and discontinued from the study. 

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The reason for the subject’s discontinuation should be documented in the electronic case 
report form (eCRF). The investigator should make every attempt to complete the 
recommended follow-up assessments specified for the End of Study/Early Termination 
visit specified in the Schedule of Events (Section 11.1
), while fully 
respecting the subject’s rights. 
In the case of a reported nerve effect leading to paresthesia or weakness, as well as any 
severe unanticipated AE that is determined to be an AE related to the device treatment, a 
root-cause investigation will be conducted to determine the cause, the outcome of the event, 
and status of subject. The investigator and the sponsor will conduct a thorough evaluation 
of the event. The sponsor will then immediately make a determination if the study should 
be suspended (Section 9.2.8). 
If a non-serious AE is unresolved at the time of the subject’s final study visit, an effort will 
be made to follow the subject until the AE is resolved or stabilized, the subject is lost to 
follow-up, or some other resolution of the event occurs. The investigator should make 
every attempt to follow all serious adverse events (SAEs) and unanticipated adverse device 
effects (UADEs) to resolution. Information on pregnancy and the outcome for any subject 
who becomes pregnant during the study will be collected. 
9.2.6.3 
Provision of Care for Subjects after Study Discontinuation 
The investigator is responsible for ensuring the adequate and safe medical care of subjects 
during the study. After the end of the study or after subject discontinuation, the sponsor 
will follow all applicable local or international regulations and guidelines with regard to 
follow-up care for subjects. The investigator will ensure that appropriate consideration is 
given to a subject’s post-study care. 
9.2.7 
Suspension or Premature Termination of a Study Site 
Study participation by individual sites may be suspended or prematurely terminated by the 
sponsor. Reasons for the suspension or premature termination of study sites include, but 
are not limited to, the following: 
• Investigator request; 
• Serious or persistent noncompliance with the protocol, local regulations, and/or GCP; 
• Suspicion of fraud; 
• Failure to accrue subjects at an acceptable rate; and/or 
• Ethical issues. 
The sponsor will provide the investigational site with written notification documenting the 
reason for suspension or premature termination. The sponsor will inform the responsible 

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regulatory authority, as appropriate, and ensure the IEC/IRB is notified. If the suspension 
or premature termination was in the interest of safety, the sponsor will inform all other 
principal investigators. 
In cases of temporary suspension at an investigational site, the sponsor will conduct an 
analysis of the reason(s) for suspension. After completing this analysis and implementing 
necessary corrective actions, a temporary site suspension may be lifted. The sponsor will 
inform the principal investigators, the IEC/IRB, and, where appropriate, the regulatory 
authority of the rationale, providing relevant data supporting this decision. Concurrence 
must be obtained from the IEC/IRB and, where appropriate, regulatory authorities before 
the investigational site resumes trial activities. If subjects were informed of the suspension, 
the principal investigator or authorized designee will inform them of the reasons for 
resumption. 
In cases of premature termination, the investigator will conduct site-closure activities in 
accordance with all applicable sponsor, local, and international guidelines and regulations. 
In the event of a pandemic disease outbreak (e.g., new COVID-19 public health 
emergency), it may not be feasible for an investigational site to continue study 
participation. In this scenario, consideration will be given to the impact of investigative-
site closure on the safety and well-being of participating subjects. 
9.2.8 
Suspension or Premature Termination of the Study 
Should the investigator, sponsor, the FDA, or local regulatory authorities become aware of 
conditions arising during the conduct of this study that may warrant cessation of the study, 
such action may be taken. Prior to such action, consultation between the sponsor, the 
investigator, and, as appropriate, the FDA and/or local regulatory authorities will occur. 
Reasons for suspension or premature termination of the study include, but are not limited 
to: 
• Determination of a potential safety risk to subjects; 
• Inadequate subject enrollment; 
• Decision by the IEC/IRB to suspend or terminate approval/favorable opinion for the 
study; and/or 
• Sponsor decision. 
If suspicion of an unacceptable risk to subjects arises during the trial or if instructed by the 
IEC/IRB or regulatory authorities, the sponsor will suspend the trial while the risk is 
assessed. If the analysis determines that implementing necessary corrective actions is 
sufficient, a temporary trial suspension may be lifted. If an unacceptable risk is confirmed, 
the sponsor will terminate the trial. 

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In the event of study suspension or premature termination, the sponsor will inform all 
investigators and relevant regulatory authorities promptly of the study suspension/ 
termination and reason for the action, as detailed in Section 9.2.7. The investigator will 
conduct site-closure activities in accordance with all applicable sponsor, local, and 
international guidelines and regulations. 
9.2.9 
Subject Completion 
Subjects are considered to have completed the study if they receive full treatment and 
complete all visits defined in the Schedule of Events (Section 11.1
). 
9.2.10 
End of Study 
The end of the study is defined as when the last subject completes the last visit and the 
database is closed. 

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10.2 Instructions for Use and Administration 
The investigational device should be used in the décolleté region in accordance with the 
information presented in Section 10.3. Additional information on product usage is 
provided in the current version of the Octave System IFU 
 
It is recommended that the following areas be avoided during treatment with the Octave 
System: 
• Thyroid gland, thyroid cartilage, and trachea; 
• Major vessels; 
• Breast tissue. 
The Octave System should only be used by those trained and qualified to operate. For this 
clinical trial, such training will be provided by the sponsor before the start of the study. 
Additionally, should study personnel change during the trial, the sponsor will retrain, as 
necessary. 
10.3 Methods of Assigning Subjects to Treatment Groups 
Subjects who provide informed consent, complete all screening assessments, meet all 
eligibility criteria, and are accepted for enrollment into the study will be assigned a unique 
subject identification number. 
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10.5.2 
Selection and Timing of Treatment for Each Subject 
At the baseline visit, all enrolled healthy, adult subjects with moderate to severe fine lines, 
wrinkles, laxity, and crepiness of the décolleté will receive a single Octave-Ultherapy 
treatment of the décolleté tissue according to the treatment guidelines presented in 
Section 10.5.1.3. No additional treatments will be offered under this study protocol. 
10.5.3 
Treatment Interruption and Modification 
If any problems occur during system operation, the treating investigator should take the 
following immediate action(s): lift the transducer off the subject’s skin, press the 
Imaging/Ready button on the handpiece or console to discontinue treatment in progress, 
and/or press the red emergency Stop button to completely halt console operation. 
As described in Section 10.5.1.2, should the subject experience escalating pain during the 
Ultherapy procedure that is not adequately controlled with the previously selected 
treatment regimen, the investigators may use their discretion to utilize further protocol-
specific options to control pain. If the pain experienced by the subject remains intolerable 
after having administered the maximum allowable limit and type of treatment medications, 
treatment should be discontinued, and the subject will be followed for safety only. 
10.6 Prior and Concomitant Therapy 
Medical history and concomitant therapies, including pre- and post-treatment pain 
measures, that are deemed relevant for study conduct by the investigator (e.g., chronic 
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according to the clinical study protocol. The sponsor will keep records to document the 
physical location of all IMDs from shipment to the investigational sites until return or 
disposal. The investigator or an authorized designee is responsible for ensuring that 
accurate records of receipt, use, return, and disposal of the IMD, are maintained and 
include: 
• Date of receipt. 
• Identification of each IMD (batch number/serial number or unique code). 
• Expiration date. 
• Date or dates of use. 
• Unique subject number. 
• Date of return of unused, expired, or malfunctioning IMD (if applicable). 
All unused investigational products must be returned to the sponsor or designee 
immediately after the study is completed. Products deliberately and/or accidentally 
destroyed during shipment or at an investigational site should be accounted for and 
documented. All clinical supplies must be accounted for at the termination of the study and 
a written explanation provided for discrepancies.  
Lastly, dispensing records of treatment lines are recorded on the subject’s treatment record, 
which is automatically generated by the Ulthera System. These data will be entered to the 
EDC system. An overall accountability log will be maintained, documenting the number 
of treatment lines per subject. 
10.10 Treatment Compliance 
The single treatment session will be administered by the treating investigator or by 
delegated and qualified study personnel. Variations from the defined study-treatment 
administration will be reported as protocol deviations. See Section 10.5.1.3 for additional 
details. 
10.11 Duration of Study 
Subjects are screened at the screening visit and enrolled and treated at the baseline visit. 
Expected study duration is approximately 8 months from screening of the first subject until 
final follow-up of the last subject. In Stage 1, an initial cohort of subjects will be enrolled, 
safety data will be assessed up to Week 2, and subjects will participate until Stage 1 study 
end at Day 90. In Stage 2, all enrolled subjects will participate for at least 90 days 
(± 7 days), with a maximum duration of 180 days (± 14 days) if reconsented for extended 
participation. The planned duration of participation for individual subjects is up to 
30 weeks, including up to 21 days for screening, 1 day for treatment, and 90 (± 7) days or 
180 (± 14) days for follow-up. 
 

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After removing any moisturizers/emollients, makeup, bronzing agents, etc. on the 
neck/décolleté region, these untreated individuals will be required to meet selected 
appearance criteria as follows: 
• Female aged 35 to 65 years. 
• Moderate to severe fine lines, wrinkles, laxity, and crepiness of the décolleté that is 
amenable to improvement with non-invasive intervention and is not severe enough for 
surgical intervention. 
• No scarring in the décolleté region. 
• No tattoos in the décolleté region. 
• No open wounds or lesions in the décolleté region. 
• No active, cystic, or severe inflammatory acne in the décolleté region. 
• No evidence of recent excessive or prolonged exposure to sunlight, tanning booths, sun 
lamps, or UV-light sources in the décolleté region. 
• No evidence of recent use of pigmenting 
agents (e.g., self-tanning agents, 
bleaching/depigmenting agents) in the décolleté region. 
• No evidence of recent medical procedures in the neck, breast, shoulder, arm, or chest 
region. 
• Willingness to avoid excessive or prolonged exposure to sunlight, tanning booths, sun 
lamps, or UV-light sources until second photo is taken. 
• Willingness to avoid the use of pigmenting agents (e.g., self-tanning agents, 
bleaching/depigmenting agents) until second photo is taken. 
• Willingness to avoid any elective neck, breast, shoulder, arm, or chest surgery, 
procedure, or treatment until after the second photo is taken. 
Untreated individuals will be screened and selected by a third-party vendor, responsible 
for conducting all photography services. Eligibility of untreated individuals will be based 
on study-specific appearance only, as listed above, and will be confirmed by the sponsor’s 
medical expert. Photographs of untreated individuals will be taken at two different time 
points, between 1 day and 1 week apart. 
Additional information on the methodological plan, detailing photograph collection 
through subsequent presentation to blinded evaluators, will be provided in a supporting 
document, developed collaboratively between the sponsor and the photography vendor. 
Results of the independent photographic review for the untreated individuals will be 
recorded. 

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11.2.1.1.2 
Photographs for Independent, Blinded Evaluation 
To assess the proportion of treated subjects with improvement in lines and wrinkles of the 
décolleté from baseline to Day 90 (i.e., primary effectiveness endpoint) and to Day 180 
(i.e., secondary effectiveness endpoint), three independent, blinded evaluators will assess 
paired, 2D photograph sets of treated subjects and untreated individuals, according to the 
procedure described below. These evaluators will be experienced, non-treating physicians, 
who are board-certified in an appropriate specialty (e.g., dermatology, plastic surgery, etc.). 
One image set, containing only the frontal view, will be paired as follows: 
• Set 1 (treated subjects only): Photograph 1 (baseline) vs. Photograph 2 (Day 90 or 
Day 180 post-treatment); 
• Set 2 (untreated individuals only): Photograph 1 (“baseline”) vs. Photograph 2 (post-
baseline). 
Photograph 1 will be identified, and the independent evaluators will be blinded to the 
random distribution of treated versus untreated status of the comparator Photograph 2 (i.e., 
Day 90 or Day 180 post-treatment among treated subjects or post-baseline for untreated 
individuals). 
For each image set, blinded evaluators will assess each photograph and will be asked the 
following: “Using Photograph 1 as a reference, which of the following best characterizes 
the change in aesthetic appearance observed in the comparator Photograph 2: Improvement 
or No Improvement.” 
Improvement will be declared if at least two blinded evaluators indicate “Improvement” 
for the comparator photograph. 
Additional information on the methodological plan, detailing photograph collection 
through subsequent presentation to blinded evaluators, will be provided in a supporting 
document, developed collaboratively between the sponsor and the photography vendor. 
This assessment will be proctored by the central photography vendor. 
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11.2.2 
Safety Assessments 
Standard safety assessments, including documentation of AEs and SAEs reported by the 
investigator throughout the study, will be evaluated. 
11.2.2.1 
Adverse Events (AEs)/Serious Adverse Events (SAEs) 
All AEs/SAEs reported by study subjects, investigators, or other study personnel after the 
time of informed consent through end of study will be recorded, regardless of causality. 
The period of observation for an AE extends from signing of the ICF through the subject’s 
last study visit. Additional information (e.g., definitions, reporting requirements) regarding 
AEs and SAEs is provided in Section 12.1 and Section 12.2, respectively. 
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11.2.3 
Additional Data Collected 
Data for other assessments will be collected as follows: 
• 
Demographics and other baseline characteristics, including FST
, 
height, and weight; 
                                                             
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• 
Urine pregnancy tests (only if subject is of childbearing potential); 
• 
Number of treatment lines administered, stratified by region and transducer; 
• 
Relevant medical history/concomitant diseases; and 
• 
Concomitant therapies. 

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12 SAFETY DEFINITIONS AND REPORTING REQUIREMENTS 
12.1 Definition of an Adverse Event (AE) 
An AE is any untoward medical occurrence, unintended disease or injury, or untoward 
clinical sign (including abnormal laboratory findings) in subjects, users, or other persons, 
whether or not related to the IMD. 
Note: 
1. This definition includes events related to the IMD. 
2. This definition includes events related to the procedures involved. 
3. For users or other persons, this definition is restricted to events related to the IMD. 
12.1.1 
Details of an AE 
The period of observation for an AE extends from when the ICF is signed until the subject’s 
last study visit. Any medical occurrence between the time the ICF is signed and the first 
treatment with the IMD is an AE and has to be documented in the subject’s file and in the 
AE eCRF. Any observed AE will be fully investigated, documented, and followed until the 
event is either resolved or adequately explained. In cases of surgical or diagnostic 
procedures, the condition/illness leading to such a procedure is considered the AE rather 
than the procedure itself. New AEs reported to the investigator during the observational 
period, after the last treatment with the IMD, must be documented, treated, and followed 
like all other AEs. 
A pre-existing condition noted in the medical history should not be reported as an AE, 
unless the condition worsens or the disease reoccurs during the reporting period. 
To determine whether a condition has worsened, it is compared to the subject’s condition 
at screening. 
Elective treatments planned before screening, and which are documented in the subject’s 
source data, are usually not regarded as AEs. However, elective procedures should be 
postponed, if possible, until the subject completes participation in the trial. 
12.1.2 
Reporting and Handling of an AE 
Data pertaining to AEs will be collected during each clinical study visit based on the 
subject’s spontaneous description, through investigator inquiry, or upon discovery in the 
course of examinations completed during the visit. The investigator will assess and record 
any AE in detail in the subject file and on the AE eCRF. The following information must 
be recorded: 

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• AE diagnosis or main symptom; 
• Affected treatment area. In case of a local reaction, the corresponding area should be 
reported; 
• Date of onset; 
• Intensity (maximum observed using the Severity Grading scale; see Section 12.1.3); 
• Causal relationship (not related, related); 
• Serious (yes or no), date serious since, and reason for seriousness; 
• Outcome (see Section 12.1.5); 
• AE leading to discontinuation of the clinical study (yes or no);  
• Action taken with medical device; and 
• Stop date. 
In cases of an SAE (defined in Section 12.2), the investigator must also complete an SAE 
Report Form and report it to the sponsor within 24 hours, as described in Section 12.2.2. 
12.1.3 
Severity Grading for an AE 
The clinical severity (i.e., intensity) of an AE will be classified as: 
Mild: 
Signs and symptoms that can be easily tolerated. Symptoms can be ignored 
and disappear when the subject is distracted. 
Moderate: Signs and symptoms that cause discomfort and interfere with normal 
functioning but are tolerable. They cannot be ignored and do not disappear 
when the subject is distracted. 
Severe: 
Signs and symptoms that affect usual daily activity and incapacitate the 
subject, thereby interrupting daily activities. 
The investigator is required to grade the severity (i.e., intensity) of each AE. 
12.1.4 
Causal Relationship of an AE with an Investigational Medical 
Device 
An AE is considered to be “related” to IMD or the treatment procedure if a causal 
relationship between the IMD or the treatment procedure and an AE is at least reasonably 
possible. In this case, the non-serious event is considered an adverse device effect (ADE; 
Section 12.3). If the event is serious, it is a serious adverse device effect (SADE; 
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The expression “reasonable causal relationship” is meant to convey that there are facts 
(evidence) or arguments to suggest a causal relationship. Otherwise, the relationship should 
be considered as “not related”. 
12.1.5 
Outcome Categories for an AE 
Reportable outcomes and/or sequelae of an AE may include the following: 
• Recovered/resolved; 
• Recovering/resolving; 
• Not recovered/not resolved; 
• Recovered/resolved with sequelae; 
• Fatal; or 
• Unknown. 
If there is more than one AE, only the AE leading to death will be attributed with a “fatal” 
outcome. 
12.2 Definition of a Serious Adverse Event (SAE) 
An SAE is an adverse event that: 
• led to death; 
• led to serious deterioration in the health of the subject, that either resulted in: 
o a life-threatening illness or injury; 
o a permanent impairment of a body structure or a body function, including 
chronic diseases; 
o inpatient or prolonged hospitalization; or 
o medical or surgical intervention to prevent life-threatening illness or injury or 
permanent impairment to a body structure or a body function. 
• led to fetal distress, fetal death, or a congenital abnormality or birth defect including 
physical or mental impairment. 
Note: Planned hospitalization for a pre-existing condition, or a procedure required by the 
clinical study protocol (CSP), without serious deterioration in health, is not considered an 
SAE. 

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12.2.1 
Details of an SAE 
In cases of fatality, the cause of death is considered the AE, and the death is considered its 
outcome. In this case, the primary cause of death (i.e., the event leading to death) should 
be recorded and reported as an SAE. “Death” will be recorded as the outcome of this 
respective event; death will not be recorded as a separate event. Only if no cause of death 
can be reported (e.g., sudden death, unexplained death), the death per se might be reported 
as an SAE. In cases of death, an autopsy report should be submitted (if available). The date 
and cause of death should be recorded. 
Planned hospitalization for a pre-existing condition is not considered an SAE. If a subject 
experiences an additional AE that prolongs a pre-planned hospitalization, this event is 
considered an SAE and should be reported as such. Hospitalizations for elective treatments 
planned before screening and which are documented in the subject’s source data are not 
regarded as SAEs. 
In addition, device deficiencies, as defined in Section 12.5, that might have led to an SAE 
if: 
• suitable action had not been taken; or 
• intervention had not been made; or 
• if circumstances had been less fortunate 
should be categorized as an SAE and reported accordingly. 
12.2.2 
Reporting and Handling of an SAE 
All SAEs that occur during the clinical study period, whether considered to be related to 
an IMD or not, must be reported via telephone or e-mail, and an SAE Report Form should 
be submitted to the sponsor immediately of knowledge of the event. Further reporting 
details will be outlined in a separate document. 
Although all information required for completion of an SAE Report Form may not be 
available within the specified time period, an initial report should be submitted if the 
following minimal information is available: 
• An identifiable subject (unique subject number); 
• A suspect product and how the treatment relates to the SAE; 
• An identifiable reporting source (investigator/study site identification); and/or 
• An event or outcome that can be identified as serious. 

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The investigator must report SAEs to Merz as defined in Section 12.2 and the site’s 
IEC/IRB per their reporting guidelines. 
Within 10 working days after Merz first receives notice of the SAE, Merz Product Safety 
will conduct an evaluation of the SAE and report the results of such evaluation to regulatory 
agencies, IECs/IRBs, and investigators, as applicable. 
The investigator must supply further supporting information, and a detailed SAE 
description is an integral part of this supporting information. Follow-up SAE reports should 
be sent without delay to the sponsor as an SAE Report Form (marked as a “follow-up” 
report), and the eCRF has to be updated accordingly to avoid discrepancies. The SAE has 
to be followed until the SAE is resolved/recovered or a plausible explanation is available. 
The SAE will be followed only in the Global Product Safety database after final SAE 
reconciliation is completed. 
An SAE occurring after the end of the observational period would need to be reported if 
the investigator considers the event to be related to IMD. These reports generally will not 
be entered into the study database. Following database close for the study, any ongoing 
SAEs will be followed until resolution or stabilization under the responsibility of the 
investigators per their standard of care. 
The investigator should complete and send any SAE Report Forms (including any follow-
up forms) to Merz North America Product Safety via the email provided below: 
Merz North America, Inc. Product Safety 
6501 Six Forks Road 
Raleigh, NC 27615 
US 
Product Safety Email: AxUS-adverse.events@merz.com 
12.3 Definition of an Adverse Device Effect (ADE) 
An ADE is defined as an AE related to the use of an IMD. 
Note: 
1. This definition includes AEs resulting from insufficient or inadequate instructions 
for use, deployment, implantation, installation, or operation or any malfunction of 
the IMD. 
2. This definition includes any event resulting from use error or from intentional 
misuse of the IMD. 

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12.4 Definition of a Serious Adverse Device Effect (SADE) 
A SADE is defined as an adverse device effect that has resulted in any of the consequences 
characteristic of an SAE (Section 12.2). 
12.4.1 
Definition of an Anticipated Serious Adverse Device Effect 
(ASADE) 
An ASADE is a serious adverse device effect which by its nature, incidence, severity, or 
outcome has been identified in the current version of the risk analysis report. 
12.4.2 
Definition of an Unanticipated Adverse Device Effect (UADE) 
A UADE is defined as follows: 
• Any serious adverse effect on health or safety or any life-threatening problem or death 
caused by, or associated with, a device, if that effect, problem, or death was not 
previously identified in nature, severity, or degree of incidence in the investigationa l 
plan or application (including a supplementary plan or application), risk analysis report, 
or IFU. 
• Any other unanticipated serious problem associated with a device that relates to the 
rights, safety, or welfare of subjects. 
12.5 Definition of Device Deficiency 
A device deficiency is defined as an inadequacy of a medical device with respect to its 
identity, quality, durability, reliability, safety, or performance. 
Note: Device deficiencies include malfunctions, use errors, and inadequate labeling. 
12.6 Definition of Technical Complaint 
A technical complaint, also referred to as a product complaint, is an apparent or suspected 
deficiency of a product in which the product does not meet its specification (e.g., console 
error, transducer failure, handpiece malfunction). 
Note: The term “technical complaint” is synonymous with the term “device deficiency”. 
The term device deficiency is used in this study. 

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12.6.1 
Reporting and Handling of Device Deficiencies  
All device deficiencies shall be documented and reported by the investigator throughout 
the clinical investigation and appropriately reported to the sponsor. 
For reporting of device deficiencies: 
• For device deficiencies related to a specific subject’s treatment, a Device Deficiency 
eCRF must be completed and submitted by the investigational site, irrespective of the 
seriousness of the case. 
• For device deficiencies related to a specific subject’s treatment, a Device Deficiency 
eCRF must be completed and submitted by the investigational site, irrespective of 
whether the complaint led to an AE. The investigator will attempt to evaluate if the 
device deficiency might have led to an AE if suitable action had not been taken, 
intervention had not been made, or circumstances had been less fortunate. 
• If a device deficiency is associated with an SAE, the investigator must also complete 
and submit an SAE Report Form (Section 12.2.2), in addition to the Device Deficiency 
eCRF. SAE Report Forms should be sent to Merz Product Safety for processing 
(Section 12.2.2). 
• If a device deficiency is not related to a specific subject (e.g., damaged transducer or 
handpiece occurring prior to the subject’s visit), the investigator should complete a 
paper device deficiency form (e.g., Device Technical Complaint Form), instead of the 
eCRF, and send to the sponsor within 24 hours to both their clinical study representative 
as well as to the Merz Technical Complaint Department for processing using the 
following email address: devicehelp@merz.com. If needed, technical complaint 
support can be reached at 877-858-4372. 
The investigator should retain the device in question for future inspection and investigation 
by the sponsor, if necessary. The Merz Technical Complaint Department will decide if the 
device in question needs to be returned and to whom it should be sent for investigation. 

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12.8 Reporting of Pregnancy 
Any pregnancy that starts during the clinical study must be reported by the investigator to 
the sponsor within 24 hours of learning of its occurrence. Pregnancy follow-up should 
describe the outcome of the pregnancy, including any voluntary or spontaneous 
discontinuation; details of the birth; the presence or absence of any congenital 
abnormalities, birth defects, maternal or newborn complications, and their relation to the 
IMD. Pregnancies and pregnancy follow-up should be reported on a Pregnancy Form; this 
form should be submitted to the contacts referenced in Section 12.2.2. In addition, each 
pregnancy has to be reported on the AE eCRF (i.e., as a non-serious AE due to device 
exposure before or during pregnancy). If subjects become pregnant during the study, they 
will remain enrolled for safety follow-up. 
 

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13 STATISTICAL METHODS 
This section describes the statistical analyses foreseen at the time of study planning. Further 
details on the statistical and analytical aspects will be presented in the statistical analysis 
plan (SAP) that will be prepared and completed prior to interim closure of the study 
database. If needed, the SAP will be updated before database close at the end of the study. 
Any deviations from planned analyses, the reasons for such deviation, and all alternative 
or additional statistical analyses that may be performed before database close will be 
described in amendments to the clinical study protocol and/or the SAP. All deviations 
and/or alterations will also be summarized in the clinical study report. 
13.1 Estimation of Sample Size 
A responder rate of 70% is assumed for the proportion of subjects with improvement from 
baseline to Day 90, as defined by the correct selection of the Day 90 standardized, 
photographic images by two of three independent, blinded evaluators. Monte-Carlo 
simulations were conducted to obtain sample sizes of evaluable subjects required to 
achieve an improvement rate of ≥ 65% and lower bound of 1-sided 95% confidence 
interval above 50%. To achieve this threshold with ≥ 85% power, a sample size of 80 
evaluable subjects will be required. Assuming a maximum attrition of 10 subjects, 
approximately 90 subjects will be enrolled. In Stage 1, 10 subjects will be enrolled, while 
all other subjects will be enrolled in Stage 2. Because a sample size of 80 subjects who 
complete the full Ultherapy treatment session is required, study enrollment will continue 
until the required number of treated subjects is achieved. 
13.2 Randomization 
No randomization procedures for treatment allocation will be used in this study. 
13.3 Populations for Analysis 
The following analysis sets will be defined for the statistical analysis of this study: 
• The Safety Population (SP) includes all subjects who are enrolled and are treated with 
the Octave System. 
• The Intent-to-Treat (ITT) population consists of all subjects who are enrolled. 
• The Per Protocol (PP) population consists of all subjects in the ITT population who 
complete the full Ultherapy treatment session using the Octave System and do not have 
a major protocol violation. 

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Gain or loss of ≥ 2 BMI units from screening to Day 90 will be considered a major protocol 
deviation. Subjects with gain or loss of ≥ 2 BMI units from screening to Day 90 will be 
excluded from PP population. The following subgroups will be defined by the change in 
body weight from screening to Day 90: 
• Subjects in ITT population with gain of ≥ 2 BMI units; 
• Subjects in ITT population with loss of ≥ 2 BMI units; and 
• Subjects in ITT population with change of < 2 BMI units. 
Primary endpoint with observed cases will be analyzed in all subgroups, as defined above, 
with more than five subjects. 
13.4.1.2 
Secondary Effectiveness Endpoint 
Note: Secondary endpoint will be assessed only among subjects reconsented for extended 
study participation. 
The proportion of subjects fulfilling the secondary endpoint will be described by frequency 
statistics for the ITT subset, including the one-sided 95% Wilson CI. 
13.4.2 
Safety Analyses 
All safety evaluations will be summarized for observed values in the SP. 
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13.4.2.1 
Secondary Safety Endpoint 
All AEs will be coded according to the Medical Dictionary for Regulatory Activities 
(MedDRA) version in effect at the time the database is closed. 
Treatment-emergent AEs (TEAEs) are defined as AEs with onset or worsening at or after 
the first administration of study treatment. In this regard, an AE, with onset prior to 
treatment, that worsens at or after first administration of study treatment must be 
documented as a new TEAE with onset at the time of worsening. 
An overall summary of AEs will be provided for the following: 
• Any AEs; 
• Any non-TEAEs; 
• Any TEAEs; 
• Any treatment-related TEAEs; 
• Any serious TEAEs, and 
• Any TEAEs leading to discontinuation. 
Incidences will be provided for the following classes of AEs: 
• TEAEs by MedDRA preferred term (PT) and system organ class (SOC); 
• TEAEs by PT; 
• TEAEs by maximum severity, maximum duration, and combination of both by PT; 
• Related TEAEs by PT and SOC; and 
• Serious TEAEs by PT and SOC, 
• Related serious TEAEs by PT and SOC. 
Moreover, incidences of TEAEs, by PT and SOC, will be provided for the following 
subgroups: Race and FST (I, II, III versus IV, V, VI). 
Listings for all AEs, as well as subsets including AEs leading to discontinuation, related 
SAEs, and deaths, will be provided. Treatments discontinued due to pain and device 
deficiencies will also be listed. 
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13.4.3 
Other Subject Data 
All demographic, baseline characteristics, and subject disposition data will be presented 
using standard descriptive statistics. Demographic data will be summarized for the SP and 
also for the ITT subset if differences exist between the two populations. 
Frequencies of concomitant treatments will be given based on different Anatomical 
Therapeutic Chemical (ATC) Classification System code levels for the SP. Indications for 
concomitant therapies will not be coded and will only be listed. 
Medical history and concomitant diseases will be coded using the MedDRA dictionary and 
reported by SOC and PT levels for the SP. Extent of exposure (lines applied by region and 
transducer) will be summarized. 
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13.5 Special Statistical/Analytical Issues 
13.5.1 
Subject Discontinuation and Missing Data 
The methods intended for handling a missing primary or secondary effectiveness endpoint 
are described in Section 13.4.1.1 and Section 13.4.1.2, respectively. 
 
For the remaining endpoints, observed cases will be analyzed, unless otherwise specified. 
13.5.2 
Interim Analysis 
In Stage 1, an initial cohort of 10 subjects will be enrolled. An interim database close and 
interim safety analysis of the first 10 subjects treated in Stage 1 will be conducted. This 
Stage 1 analysis will contain Week 2 safety data for the first 10 subjects treated. Safety 
analyses will be performed on the SP. Effectiveness data will not be included in the interim 
analysis. 
Continuation to Stage 2 will be paused during evaluation of the Week 2 safety data from 
the first 10 subjects treated. All 10 subjects enrolled in Stage 1 will participate until Stage 1 
study end, for a maximum duration of 90 days (± 7 days). 
The interim analysis is only intended to obtain safety data for the first 10 subjects treated 
before starting recruitment for Stage 2. The interim analysis is not proposed to modify the 
study design, statistical analyses, or sample size, or for study termination, as this is not an 
adaptive study design. Since no effectiveness data are analyzed at interim, the interim 
analysis will not compromise the integrity of the study’s effectiveness data, and it will not 
bias the final effectiveness analysis. 
 

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14 ADMINISTRATIVE PROCEDURES 
14.1 Study Monitoring 
Study monitoring will conform to all applicable regulatory standards and guidelines. 
The sponsor or designee will monitor the study through periodic site visits to verify: 
• Data authenticity, accuracy, and completeness; 
• Protection of subject rights and safety; and 
• Conduct of the study is in accordance with the currently approved protocol and all 
applicatory regulatory requirements and guidelines. 
Investigators agree to grant access to all relevant documents and provide support at all 
times for study monitoring activities. Study monitoring activities will be performed in a 
manner that ensures maintenance of subject confidentiality (Section 5.3 and Section 5.4). 
Further details of monitoring activities will be described in the monitoring manual. 
14.2 Data Quality Assurance 
Inspections by regulatory authority representatives and IECs/IRBs are possible at any time, 
even after the end of study. The investigator is to notify the sponsor immediately of any 
such inspection. The investigator and institution will permit study-related monitoring, 
audits, reviews by the IEC/IRB and/or regulatory authorities, and will allow direct access 
to source data and source documents for such monitoring, audits, and reviews. 
14.2.1 
Standardization Procedures 
Standardization procedures will be implemented to ensure accurate, consistent, complete, 
and reliable data, including methods to ensure standardization among sites (e.g., training, 
newsletters, investigator meetings, monitoring, evaluations, and validation methods). 
Standardized photography methods will be detailed in a separate photography user manual. 
This study will be monitored regularly by a qualified monitor from the CRO according to 
GCP guidelines and the respective standard operating procedures (SOPs; see Section 14.1). 
14.2.2 
Data Management 
Data required according to this protocol are to be recorded in the web-based eCRFs 
provided by a CRO. All users who will enter data into the eCRF must successfully 
complete training before system access is granted. Participant training will be documented. 
Access to the eCRF will be password controlled and will conform with 21 CFR Part 11. 

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Data-plausibility checks will be performed according to a data validation plan. 
Inconsistencies in the data will be queried to the investigators via the EDC system; answers 
to queries or changes to the data will also be documented in this system directly by an 
authorized member of the investigator’s study personnel. The audit trail in the EDC system 
will document all changes. Edit checks generate automatic queries during data entry when 
a field is not populated according to specifications defined in the data validation plan. 
Manual queries to be answered by study personnel can be raised during source data 
verification and/or during medical, safety, and/or data management review. 
Photographs will be archived by the central photography vendor in a system separate from 
the database (see Section 14.3). 
photo ratings by 
independent, blinded 
investigators will be transferred electronically 
to the data 
management CRO. Checks will be performed to ensure plausibility and completeness of 
these data. The data management activities and photograph processing will be delegated to 
 CROs 
 
After all necessary data for the interim safety analysis of the first 10 subjects enrolled in 
Stage 1 have been entered and cleaned, an interim database close will be performed. 
The database will be closed after all subjects have completed their Day 90 visit and again 
after completion of their Day 180 visit. Hence, after all applicable data are entered, 
monitored, and verified, and all queries are solved, the database will be closed. After 
database close at Day 90, the relevant pages will remain locked for further data entry and/or 
update. If data changes are needed after database close, they will be documented according 
to the respective SOP. The same requirements apply for the Day 180 database lock. 
For the final analysis, after all data are entered and all queries are resolved, the database 
will be closed again. If any data changes are required after database close, these changes 
will be documented according to the respective SOP. 
Further details of the data management process will be described in the data management 
plan. 
14.2.3 
Data Review and Clarification Procedures 
By electronically signing the eCRF with an automated time stamp, the investigator will 
confirm that all investigations have been completed and conducted in compliance with the 
CSP and that reliable and complete data have been entered into the eCRF. 
All data required by this CSP are to be recorded in the eCRF as soon as possible. However, 
direct entries are not allowed; data must be transcribed from the source documentation 
(e.g., subject file, scales) to the eCRF. 

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All data required by this study protocol, except photography ratings
, are 
to be entered into a sponsor-validated database of eCRFs. 
If corrections are necessary, an authorized member of the investigator’s study personnel 
will enter the correct data into the web-based eCRF. The audit trail in the EDC system 
documents all changes. 
The CRO and sponsor’s data management function will be responsible for data processing, 
in accordance with the CRO’s and sponsor’s data management procedures. Database close 
will occur only after quality assurance procedures have been completed. 
Entries from questionnaires completed by the subject will be entered into the eCRF by 
study personnel. If corrections in the questionnaires are necessary, the subject should be 
instructed to make a correction by drawing only a single line through the error, leaving the 
incorrect entry legible. The subject should date and initial the correction. The investigator 
should not make any changes to these documents. 
14.2.4 
Auditing 
To ensure compliance with applicable standards and regulations, the sponsor, IEC/IRB, or 
regulatory authorities may conduct a quality assurance assessment or audit of site records 
at any time during or after completion of the study. In the event of an audit, investigators 
must grant access to all relevant documents (including source documents, electronic 
records, and other applicable study documentation) and provide support at all times for 
auditing activities. 
14.3 Record Retention 
Essential documents should be retained per applicable regulations and as instructed by the 
study sponsor. Essential documents at the investigational site include but are not limited 
to: 
• Source documentation (e.g., subject files); 
• Subject identification code list (i.e., provided by template to the investigator, along with 
the Investigator Site File, at the beginning of the investigation), which identifies the 
subject by number, name, and date of birth; 
• A copy of the study protocol and any amendments; 
• A CD/DVD with eCRF data and any associated subject-related source data (or, where 
applicable, authorized copies of source data); 
• Signed ICFs; 
• Copies of site investigators’ and co-workers’ curricula vitae; 

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• Copies of all direct correspondence with the IEC/IRB and with the regulatory 
authority(ies); 
• Copies of all relevant correspondence between the investigator and the monitor, and 
between the investigator and the sponsor; 
• Copies of any photographs; 
• Copies of IMD receipt forms and device inventory forms; and 
• Copies of safety information reported during the investigation and submitted by the 
sponsor. 
Study documents may not be destroyed by study-site personnel prior to the end of the 
required retention period as specified by local regulations. The investigator or the 
institution must inform the sponsor in due time if the investigator leaves the institution 
during the retention period. This rule also applies when the institution closes within the 
retention period. 
Upon closure of the study, the investigator must maintain all study-site records in a safe 
and secure location. The investigator is responsible for the integrity, retention, and security 
of all study-related records. The investigator must ensure that any reproductions of the 
original records are legible and provide a true and accurate copy of the original. Accurate, 
complete, and current records must be stored in such a way as to permit easy and timely 
retrieval for the sponsor or any applicable regulatory authorities. 
The sponsor will inform the investigator of the time period for retaining these records to 
comply with all applicable regulatory requirements, with the minimum retention time being 
the longest of those times dictated by institutional requirements, local laws or regulations, 
or the sponsor’s standard procedures. The investigator must notify the sponsor in the event 
of any changes to archival arrangements due to withdrawal of the investigator’s 
responsibility for keeping study records to ensure that suitable arrangements for the 
retention of study records are made. 
14.4 Publication Policy 
The results of this study and any discoveries related to this study, regardless of whether 
they have technical or medical character, are the property of the sponsor. 
The CSP, study data, and information related to the study or the sponsor’s products or 
research programs are to be kept confidential and may not be disclosed without the consent 
of the sponsor. 
The investigator agrees that the results of this study may be used for submission to national 
or international registration and supervising authorities. The sponsor may disclose the 
information obtained during the study to regulatory authorities or other personnel as 

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required. If necessary, the sponsor may disclose the names, contact information, and 
qualifications of all investigators as well as their roles in the study. Upon completion of the 
study, publication or disclosure of the study results is to follow the terms contained in the 
sponsor’s SOP. 
The sponsor will ensure that a description of this clinical study is registered, and study 
results are disclosed on http://www.ClinicalTrials.gov, as required by US law. Study 
registration may include a list of study sites, as applicable. 
14.5 Financial Disclosure 
The US FDA Financial Disclosure by Clinical Investigators (21 CFR 54) regulations 
require sponsors to obtain certain financial information from investigators participating in 
covered clinical studies. By participating in the study, the investigator agrees to provide 
the required financial information and to promptly update the sponsor with any relevant 
changes to this financial information throughout the course of the study and for up to 
one year after its completion if necessary. 
14.6 Investigator Compliance 
The investigator will conduct the study in compliance with the protocol provided by the 
sponsor and in accordance with all relevant regulatory guidelines and requirements. 
Modifications to the protocol should not be made without the agreement of the investigator 
and sponsor. The sponsor will submit all protocol modifications to the appropriate 
regulatory authority in accordance with applicable regulations. All protocol modifications 
require written IEC/IRB approval/favorable opinion, except in the case of an immediate 
hazard to subjects. 
If an immediate deviation from the protocol is required to eliminate an immediate hazard 
to subjects, the investigator must contact the sponsor or assigned CRO, if possible, to 
discuss the planned course of action. The investigator must thoroughly document any 
departure from the protocol and submit appropriate documentation to the sponsor without 
delay. 
 

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16 APPENDICES