Prospective, Evaluator-blind, Multicenter Study to Assess the Safety and Effectiveness of Treatment With the Octave System for Lifting the Eyebrow and Improving the Appearance of the Face and Neck
Phase: NA
Conditions: Eyebrow Lift, Improved Appearance of the Face and Neck
Sponsor: Merz North America, Inc.

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1 TITLE PAGE 
Prospective, evaluator-blind, multicenter study to 
assess the safety and effectiveness of treatment with 
the Octave System for lifting the eyebrow and improving 
the appearance of the face and neck 
Study Identifier: 
Version Date: 
Investigational Medical 
Device: 
Indication: 
Study Design: 
Sponsor: 
M960101001 / NCT05067504
16-NOV-2021 (version 6.0; Amendment 5)
15-OCT-2021 (version 5.0; Amendment 4) 
17-AUG-2021 (version 4.0; Amendment 3) 
01-APR-2021 (version 3.0; Amendment 2) 
18-FEB-2021 (version 2.0; Amendment 1) 
10-NOV-2020 (version 1.0) 
Octave System 
Eyebrow lift; improved appearance of the face and neck 
Prospective, multicenter, evaluator-blind, staged, 180-day 
confirmatory study 
Ulthera, Inc., a division of Merz North America, Inc. / Merz 
Aesthetics 
CONFIDENTIAL AND PROPRIETARY 
The contents of this document are confidential and proprietary of Merz North America, Inc. 
Unauthorized use, disclosure or reproduction is strictly prohibited. This document or parts thereof may not 
be disclosed to parties not associated with the clinical investigation without the prior written consent of 
Merz North America, Inc. 
Document References (For Internal Use Only) 
 
 
 
 
 
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2 SYNOPSIS 
Title of Study 
Prospective, evaluator-blind, multicenter study to assess the safety and 
effectiveness of treatment with the Octave System for lifting the eyebrow and 
improving the appearance of the face and neck 
Study Identifier 
M960101001 
Number of Sites 
and Countries 
This study will be conducted at up to five investigational sites in the United 
States. 
Investigational 
Medical Device 
Octave System 
Indication 
Eyebrow lift; improved appearance of the face and neck 
Objective 
Primary objective: To demonstrate the effectiveness and safety of the Octave 
System to lift the eyebrow. 
Secondary objective: To demonstrate the effectiveness and safety of the 
Octave System to improve the appearance of the face and neck. 
Effectiveness 
Evaluation 
Primary endpoint 
•
Proportion of treated subjects with eyebrow lift, as demonstrated by
comparing photographs taken at Day 90 (post-treatment) with baseline
(pre-treatment) photographs.
o
Lift is concluded if at least two of three independent, blinded
evaluators report “eyebrow lift” in the Day 90 standardized,
photographic images when compared to baseline photographic
images.
Secondary endpoints 
•
Proportion of treated subjects with eyebrow lift, as demonstrated by
comparing photographs taken at Day 180 (post-treatment) with 
baseline (pre-treatment) photographs.  
•
Proportion of treated subjects with eyebrow lift of at least 0.5 mm on
frontal 2D photographs at Day 90 and Day 180 compared to baseline.
•
Change from baseline in FACE-Q™ Satisfaction with Forehead and
Eyebrows score (Rasch-transformed) at Day 90 and Day 180, as
assessed by the subject.
•
Change from baseline in FACE-Q Satisfaction with Lower Face and
Jawline score (Rasch-transformed) at Day 90 and Day 180, as assessed
by the subject.
•
Change from baseline in FACE-Q Patient-perceived Age Visual
Analogue Scale (VAS) rating at Day 90 and Day 180, as assessed by
the subject.

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Safety 
Evaluation 
Secondary endpoint 
•
Incidence of treatment-emergent adverse events (TEAEs), related to
Octave-Ultherapy treatment, as reported throughout the study.
Study Design 
Overview and 
Methodology 
This is a 180-day, prospective, evaluator-blind, multicenter, staged, 
confirmatory study designed to evaluate the safety and effectiveness of the 
Octave System in treating the brow, face, and neck to lift the eyebrow and to 
improve the appearance of the face and neck. 
All enrolled healthy, adult subjects will receive a single Octave-Ultherapy 
treatment of the brow, face, and neck. In Stage 1, an initial cohort of 
10 subjects will be treated with one transducer at energy level 4 
 and one transducer at energy level 2 
 In Stage 2, the remaining 
subjects will be treated with three transducers at energy level 4 
 
 and one transducer at energy 
level 2 
 The majority of subjects 
will be followed for 180 days; only those Stage 1 subjects who do not 
reconsent for extended participation will be followed for 90 days, and 
photographs will be taken at baseline, Day 90, and Day 180. 
For the primary endpoint, the proportion of subjects with eyebrow lift will be 
determined by a blinded, independent assessment of photographs at 90 days 
post-treatment compared to baseline. The same photograph comparison will 
be made at 180 days post-treatment, as a 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. Secondary 
effectiveness evaluations will also include quantitative measurement of 
eyebrow lift and three FACE-Q modules (i.e., Satisfaction with Forehead and 
Eyebrows; Satisfaction with Lower Face and Jawline, and Patient-perceived 
Age VAS). 
Study subjects will have approximately 4 on-site 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 to Day 14, 
and subjects will participate until study end at Day 90 or Day 180 if 
reconsented for extended participation. In Stage 2, all enrolled subjects will 
participate until study end at Day 180. 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. 
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Number of 
Study Subjects 
Approximately 60 subjects are planned for screening to allow for 
approximately 50 enrolled/treated subjects and approximately 40 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 male or female aged 35 to 65 years at the time of screening.
−
Mild to moderate eyebrow/upper-face laxity that is amenable to
improvement with non-invasive intervention and is not severe enough
for surgical intervention.
−
Mild to moderate fine lines, wrinkles, and laxity of the face and neck
that are amenable to improvement with non-invasive intervention and
are not severe enough for surgical intervention.
−
−
Subject meets Octave System ultrasound-imaging criteria in the
intended lower face and neck treatment regions, ensuring soft tissue is
visualized at a depth of at least 3.0 mm.
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.
−
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..................................................................................... 8 
4 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ..................... 13 
5 
ETHICS ............................................................................................................. 16 
5.1 
Ethical Conduct of the Study ............................................................................ 16 
5.2 
Informed Consent ............................................................................................ 16 
5.3 
Subject Privacy ................................................................................................ 17 
5.4 
Confidentiality of Subject Information .............................................................. 17 
6 
INTRODUCTION ............................................................................................. 18 
6.1 
Background ..................................................................................................... 18 
6.2 
Study Rationale................................................................................................ 22 
6.3 
Potential Benefits and Risks ............................................................................. 22 
7 
STUDY OBJECTIVE AND ENDPOINTS ........................................................ 25 
7.1 
Objective ......................................................................................................... 25 
7.2 
Endpoints ........................................................................................................ 25 
7.2.1 
Effectiveness Endpoints.............................................................................. 25 
7.2.1.1 
Primary Effectiveness Endpoint............................................................ 25 
7.2.1.2 
Secondary Effectiveness Endpoints ....................................................... 25 
7.2.2 
Safety Endpoints ........................................................................................ 28 
7.2.2.1 
Secondary Safety Endpoint ................................................................... 28 
8 
CLINICAL INVESTIGATION PLAN.............................................................. 29 
8.1 
Overview of Study Design................................................................................ 29 
8.2 
Discussion of Study Design, Including the Choice of Control Groups ................ 30 
9 
STUDY POPULATION AND RESTRICTIONS .............................................. 32 
9.1 
Number of Subjects and Sites ........................................................................... 32 
9.2 
Selection of Subject Population ........................................................................ 32 
9.2.1 
Inclusion Criteria........................................................................................ 33 
9.2.2 
Exclusion Criteria ...................................................................................... 34 
9.2.4 
Subject Enrollment ..................................................................................... 38 
9.2.5 
Screen Failures........................................................................................... 38 
9.2.6 
Removal of Subjects from Therapy or Assessment ...................................... 38 
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9.2.6.1 
Treatment Discontinuation ................................................................... 38 
9.2.6.2 
Subject Withdrawal or Discontinuation ................................................ 39 
9.2.6.3 
Provision of Care for Subjects after Study Discontinuation ................... 40 
9.2.7 
Suspension or Premature Termination of a Study Site .................................. 40 
9.2.8 
Suspension or Premature Termination of the Study...................................... 41 
9.2.9 
Subject Completion .................................................................................... 42 
9.2.10 
End of Study .............................................................................................. 42 
10 STUDY DEVICE AND TREATMENT OF SUBJECTS................................... 43 
10.1 
Description of Study Device ............................................................................. 43 
10.1.1 
Mechanism of Action ................................................................................. 44 
10.1.2 
Operating Information ................................................................................ 44 
10.2 
Instructions for Use and Administration ............................................................ 46 
10.3 
Methods of Assigning Subjects to Treatment Groups ........................................ 47 
10.4 
Blinding Procedures ......................................................................................... 47 
10.5 
Study Treatment............................................................................................... 47 
10.5.1 
Planned Treatment Procedure and Administration ....................................... 47 
10.5.1.1 
Pre-Treatment Assessments .................................................................. 48 
10.5.1.2 
Pre-Treatment Medications and Procedure .......................................... 48 
10.5.1.3 
Treatment Region and Administration Procedure.................................. 49 
10.5.2 
Selection and Timing of Treatment for Each Subject ................................... 56 
10.5.3 
Treatment Interruption and Modification..................................................... 57 
10.6 
Prior and Concomitant Therapy ........................................................................ 57 
10.7 
Study Supplies and Packaging of Treatment Supplies ........................................ 57 
10.8 
Receipt, Storage, Dispensing, and Return/Disposal ........................................... 57 
10.9 
Device Accountability Procedures .................................................................... 58 
10.10 Treatment Compliance ..................................................................................... 59 
10.11 Duration of Study............................................................................................. 59 
11 STUDY PROCEDURES.................................................................................... 60 
11.1 
Visit Schedule.................................................................................................. 60 
11.1.1 
Scheduled Visits......................................................................................... 61 
11.1.2 
Unscheduled Visits..................................................................................... 61 
11.2 
Study Assessments and Definitions................................................................... 62 
11.2.1 
Effectiveness Assessments.......................................................................... 62 
11.2.1.1 
Standardized 2D Photographs.............................................................. 62 
11.2.1.2 
Secondary Effectiveness Assessments.................................................... 65 
11.2.2 
Safety Assessments .................................................................................... 67 
11.2.2.1 
Adverse Events (AEs)/Serious Adverse Events (SAEs) ........................... 67 
11.2.3 
Additional Data Collected........................................................................... 69 
12 SAFETY DEFINITIONS AND REPORTING REQUIREMENTS .................. 71 
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12.1 
Definition of an Adverse Event (AE) ................................................................ 71 
12.1.1 
Details of an AE ......................................................................................... 71 
12.1.2 
Reporting and Handling of an AE ............................................................... 71 
12.1.3 
Severity Grading for an AE ........................................................................ 72 
12.1.4 
Causal Relationship of an AE with an Investigational Medical Device ......... 72 
12.1.5 
Outcome Categories for an AE ................................................................... 73 
12.2 
Definition of a Serious Adverse Event (SAE).................................................... 73 
12.2.1 
Details of an SAE....................................................................................... 74 
12.2.2 
Reporting and Handling of an SAE ............................................................. 74 
12.3 
Definition of an Adverse Device Effect (ADE) ................................................. 75 
12.4 
Definition of a Serious Adverse Device Effect (SADE) ..................................... 76 
12.4.1 
Definition of an Anticipated Serious Adverse Device Effect (ASADE) ........ 76 
12.4.2 
Definition of an Unanticipated Adverse Device Effect (UADE) ................... 76 
12.5 
Definition of Device Deficiency ....................................................................... 76 
12.6 
Definition of Technical Complaint.................................................................... 76 
12.6.1 
Reporting and Handling of Device Deficiencies .......................................... 77 
12.7 
Adverse Events of Interest (AEI) ...................................................................... 77 
12.9 
Reporting of Pregnancy .................................................................................... 78 
13 STATISTICAL METHODS .............................................................................. 80 
13.1 
Estimation of Sample Size................................................................................ 80 
13.2 
Randomization................................................................................................. 80 
13.3 
Populations for Analysis................................................................................... 80 
13.4 
Analysis of Study Data..................................................................................... 81 
13.4.1 
Effectiveness Analyses ............................................................................... 81 
13.4.1.1 
Primary Effectiveness Endpoint............................................................ 81 
13.4.1.2 
Secondary Effectiveness Endpoints ....................................................... 82 
13.4.2 
Safety Analyses.......................................................................................... 85 
13.4.2.1 
Secondary Safety Endpoint ................................................................... 85 
13.4.3 
Other Subject Data ..................................................................................... 86 
13.5 
Special Statistical/Analytical Issues .................................................................. 87 
13.5.1 
Subject Discontinuation and Missing Data .................................................. 87 
13.5.2 
Interim Analysis ......................................................................................... 87 
13.5.3 
Data Monitoring Committee ....................................................................... 88 
14 ADMINISTRATIVE PROCEDURES............................................................... 89 
14.1 
Study Monitoring ............................................................................................. 89 
14.2 
Data Quality Assurance .................................................................................... 89 
14.2.1 
Standardization Procedures......................................................................... 89 
14.2.2 
Data Management ...................................................................................... 90 
14.2.3 
Data Review and Clarification Procedures................................................... 90 
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14.2.4 
Auditing..................................................................................................... 91 
14.3 
Record Retention ............................................................................................. 91 
14.4 
Publication Policy ............................................................................................ 92 
14.5 
Financial Disclosure......................................................................................... 93 
14.6 
Investigator Compliance................................................................................... 93 
15 REFERENCES .................................................................................................. 94 
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4 LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Definition 
2D 
Two-dimensional 
ADE 
Adverse device effect 
AE 
Adverse event 
ASADE 
Anticipated serious adverse device effect 
ATC 
Anatomical Therapeutic Chemical classification system of the World Health 
Organization 
BL 
Baseline 
BMI 
Body mass index 
CD 
Compact disc 
CFR 
Code of Federal Regulations 
CI 
Confidence interval 
COVID-19 
Coronavirus disease 2019 
CRO 
Contract research organization 
CSP 
Clinical study protocol 
DMC 
Data Monitoring Committee 
DS 
DeepSEE 
DVD 
Digital versatile disc 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
EL 
Energy level 
FACE-Q™ 
Set of subject-reported questionnaire modules 
FCS LOGISTIC 
Fully conditional specification logistic regression method 
FDA 
Food and Drug Administration (US) 
FST 
Fitzpatrick skin type 
GCP 
Good Clinical Practice 
GDPR 
General Data Protection Regulation 
H&E 
Hematoxylin and eosin 
HIPAA 
Health Insurance Portability and Accountability Act of 1996 (US) 
ICF 
Informed consent form 
ICH 
International Conference on Harmonization of Technical Requirements for 
Registration of Pharmaceuticals for Human Use 
ID 
Investigational device (term used interchangeably with investigational medical 
device (IMD)) 
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Abbreviation 
Definition 
IEC 
Independent ethics committee 
IFU 
Instructions for Use 
IM 
Intramuscular, as in treatment administration route 
IMD 
Investigational medical device (term used interchangeably with Investigational 
Device (ID)) 
IRB 
Institutional Review Board 
ISO 
International Organization for Standardization (EN = English translation) 
ITT 
Intent to treat 
MedDRA 
Medical Dictionary for Regulatory Activities 
MFU-V 
Microfocused ultrasound with visualization 
n 
Number of non-missing observations 
NRS 
Numerical Rating Scale 
NSAIDs 
Nonsteroidal anti-inflammatory drugs 
OT 
Octave System transducer 
PHI 
Protected health information 
PO 
Per os (Latin); used in medicine to describe treatment administration by oral 
route 
PP 
Per protocol 
PT 
Preferred term 
SADE 
Serious adverse device effect 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SAS 
Statistical Analysis Software® 
Scr 
Screening 
SD 
Standard deviation 
SOC 
System organ class 
SOP 
Standard operating procedure 
SP 
Safety population 
SPF 
Sun protection factor 
SSQ 
Subject Satisfaction Questionnaire 
TCP 
Thermal coagulation point 
TEAE 
Treatment-emergent adverse event 
TESAE 
Treatment-emergent serious adverse event 
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Abbreviation 
Definition 
UADE 
Unanticipated adverse device effect 
US 
United States 
UV 
Ultraviolet 
VAS 
Visual analogue scale 

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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. Long considered the gold standards, 
rhytidectomy and surgical brow lift are effective, long-term solutions for improving 
aesthetics of the aging face. However, more recently, there has been a focus on achieving 
skin tightening approximating that of a surgical face and brow lift without the associated 
possible complications or extended recovery.[1] 
The anti-aging market is rapidly advancing to accommodate the growing demand for such 
methods of skin lifting and tightening.[2, 3] As a result, many products and procedures 
have been developed to treat facial rhytids and skin laxity. Traditional ablative chemical 
peels and mechanical dermabrasion were some of the original approaches to skin 
tightening.[4] The development of full-face laser ablation treatments followed,[5] but its 
use has been limited 
by potential side effects and extended recovery time.[6] 
Microneedling has also been introduced to improve the signs of skin aging, but this 
technique requires several sequential treatments and results may take up to one year.[7] 
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.[8] 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.[9] 
This characteristic of microfocused ultrasound is particularly beneficial in patients of 
higher Fitzpatrick skin types (FST III to VI)[10], 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.[11] 
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) 
in the deep reticular layer of the dermis and subdermis, while leaving the epidermal layers 
and overlying papillary dermis unaffected.[12] These thermal micro-injuries lead to 

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collagen scaffold remodeling, which lifts the overlying skin and tightens the dermal 
layers.[12] Under the current clearance, DeepSEE® transducers are used in combination 
with the Ulthera System to incorporate high-resolution ultrasound imaging with ultrasound 
therapy. Using this ultrasonic visualization enables operator avoidance of ultrasound-
energy contact with large vessels and bone, as the technology can image to a tissue depth 
of 8 mm. 
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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 lifting the eyebrow and improving the appearance of the face and 
neck. A gradual descent of the brows and lateral hooding of the upper lids can occur 
throughout the aging process due to the effects of gravity and reduction of tissue elasticity. 
This descent results in an angry and/or tired appearance and can also cause functional visual 
impairment.[13] Ultherapy treats lax facial tissue and offers a non-invasive approach to 
improving the aesthetic appearance of the eyebrow, face, and neck regions. Subjects with 
mild to moderate eyebrow/upper-face laxity and fine lines, wrinkles, and laxity of the lower 
face and neck that are amenable to improvement with non-invasive intervention and are 
not severe enough for surgical intervention will be treated. Subjects will receive one 
Octave-Ultherapy treatment of the brow, face, and neck and will be followed for 90 or 
180 days. Previous studies have shown improvement in the aesthetic appearance of the 
eyebrow area 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 in Stage 1 will be treated with one Octave System transducer at energy level 4 
 and one Octave System transducer at energy 
level 2 
. Subjects in Stage 2 will be treated with three 
Octave System transducers at energy level 4 
 
 
and one Octave System transducer at energy level 2 
 The 
treatment maps used in both Stages 1 and 2 are similar to those used in prior studies. 
6.3 
Potential Benefits and Risks 
The potential benefit of Ultherapy on the Octave System is lifting of the eyebrow region 
and improving the appearance of the face and neck. Additionally, the results of this study 
may contribute to further development of the ultrasound-based, non-invasive, tissue-
tightening procedure. 
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Potential risks associated with the use of Ultherapy on the Octave System include localized 
acute and/or post-procedure pain or discomfort, erythema (redness), edema (swelling), 
wheals, tenderness to touch, bruising, and temporary nerve effects. Pre-treatment 
medications proposed for use in this study can cause nausea, lightheadedness, stomach 
upset, and constipation (Section 10.5.1.2). 
The rare possibility for burns, which may or may not result in permanent scar formation, 
may occur if incorrect treatment technique is used (e.g., tilting transducer, poor transducer 
to skin coupling, incorrect line spacing, gel pockets). Some scars may respond to medical 
treatment. All investigational sites will be trained on correct treatment technique. 
The following adverse events (AEs) have been identified during routine, post-market 
clinical use of the Ulthera DeepSEE System: pain; burns or burning sensation; 
edema/swelling; nodules; bruising; fat/volume loss; neuropathy; numbness; paresthesia; 
palsy; paresis; speech difficulty; muscle weakness; headache; migraine; visual change; skin 
sagging/drooping; asymmetry; erythema; welts; hives; rash; urticaria; pruritus; blistering; 
scarring; discoloration; and hyperpigmentation. These AEs were chosen for inclusion in 
the Ulthera DeepSEE System Instructions for Use (IFU) due to a combination of their 
seriousness, frequency of reporting, or potential causal connection to the Ulthera DeepSEE 
System. However, 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 AEs were 
generally expected, mild in nature, and short in duration.[2, 9, 14, 15] Long-term follow-
up studies confirmed the favorable safety profile of the Ulthera DeepSEE System with 
primarily mild, treatment-related side effects.[12] 
Risks of treatment with the second-generation Ulthera 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.[12] 
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 treating 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. 

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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 a lift of the 
eyebrow region and improved appearance of the face and neck. 
Additional information on device- and procedure-related contraindications, warnings, and 
precautions can be found in the current version of the Octave Clinical IFU 
 
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7 STUDY OBJECTIVE AND ENDPOINTS 
7.1 
Objective 
Primary objective: To demonstrate the effectiveness and safety of the Octave System to lift 
the eyebrow. 
Secondary objective: To demonstrate the effectiveness and safety of the Octave System to 
improve the appearance of the face and neck. 
7.2 
Endpoints 
7.2.1 
Effectiveness Endpoints 
7.2.1.1 
Primary Effectiveness Endpoint 
• Proportion of treated subjects with eyebrow lift, as demonstrated by comparing 
photographs taken at Day 90 (post-treatment) with baseline (pre-treatment) 
photographs. 
o Lift is concluded if at least two of three independent, blinded evaluators report 
“eyebrow lift” in the Day 90 standardized, photographic images when 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 subjects with eyebrow lift. 
7.2.1.2 
Secondary Effectiveness Endpoints 
• Proportion of treated subjects with eyebrow lift, as demonstrated by comparing 
photographs taken at Day 180 (post-treatment) with baseline (pre-treatment) 
photographs. 
• Proportion of treated subjects with eyebrow lift of at least 0.5 mm on frontal 2D 
photographs at Day 90 and Day 180 compared to baseline. 
• Change from baseline in FACE-Q™ Satisfaction with Forehead and Eyebrows score 
(Rasch-transformed) at Day 90 and Day 180, as assessed by the subject. 
• Change from baseline in FACE-Q Satisfaction with Lower Face and Jawline score 
(Rasch-transformed) at Day 90 and Day 180, as assessed by the subject. 

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• Change from baseline in FACE-Q Patient-perceived Age Visual Analogue Scale 
(VAS) rating at Day 90 and Day 180, as assessed by the subject. 
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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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8 CLINICAL INVESTIGATION PLAN 
8.1 
Overview of Study Design 
This is a 180-day, prospective, evaluator-blind, multicenter, staged, confirmatory study 
designed to evaluate the safety and effectiveness of the Octave System in lifting the brow 
and improving the appearance of the face and neck. Approximately 50 subjects will be 
enrolled at up to five investigational sites in the United States. 
All FST will be eligible for study enrollment. It is estimated that approximately 85% of the 
total sample size will consist of subjects with a FST I, II, or III, and approximately 15% of 
subjects will be FST IV, V, or VI. Subjects enrolled will be healthy male or female subjects, 
aged 35 to 65 years at the time of screening, with mild to moderate eyebrow/upper-face 
laxity and fine lines, wrinkles, and laxity of the mid- to lower face and neck that are 
amenable to improvement with non-invasive intervention and are not severe enough for 
surgical intervention. Prior to study start, all investigators will be trained on appropriate 
enrollment criteria, focused on mild to moderate eyebrow/upper-face laxity and fine lines, 
wrinkles, and laxity of the mid to lower face and neck, using photo booklets. Additiona lly, 
for each site, approximately the first four to five subjects with mild to moderate 
eyebrow/upper-face laxity and fine lines, wrinkles, and laxity of the mid to lower face and 
neck, as selected by the investigator for potential enrollment, will be confirmed for study-
appropriate laxity, lines, and wrinkles via an independent photographic reviewer. 
In this non-comparative, staged, confirmatory study, investigators and subjects will not be 
blinded to treatment, subjects will not be randomized, and all enrolled subjects will receive 
a single Octave-Ultherapy treatment of the brow, upper, mid, and lower face, and neck. 
Subjects in Stage 1 (n = 10) will receive treatment with one transducer 
 at energy level 4 and one transducer 
 at energy level 2. 
Remaining subjects in Stage 2 will receive treatment with three transducers 
 at energy level 4 and one 
transducer 
at energy level 2. In Stage 1, an initial cohort of subjects 
will be enrolled, safety data will be assessed to Day 14, and subjects will participate until 
study end at Day 90 or Day 180 if reconsented for extended participation. In Stage 2, all 
enrolled subjects will be followed for 180 days. In addition, to reduce potential bias 
associated with using only treated-subject photographs for evaluation, photographs of 
approximately 
25 untreated individuals, 
who meet selected appearance criteria 
(Section 11.2.1.1.1), will be collected at two different time points and subsequently paired 
for evaluation by the independent, blinded evaluators. Using this 2:1 ratio of treated 
subjects to untreated individuals, image sets of these untreated individuals will be randomly 
distributed among the pre- and post-treatment image sets of the treated subjects and 
presented to the blinded evaluators. For the primary effectiveness endpoint, the “baseline” 
photograph will be identified as “Photograph 1”, and the independent evaluators will be 
blinded to the randomly distributed treated versus untreated status of the comparator 
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Photograph 2 (i.e., Day 90 post-treatment among treated subjects or post-baseline for 
untreated individuals). The same photographic assessment will be used for the secondary 
effectiveness endpoint with the comparator Photograph 2 collected at Day 180 post-
treatment. 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. 
Study subjects will have approximately 4 on-site 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. The primary effectiveness endpoint, the proportion of treated 
subjects with eyebrow lift, will be evaluated using a blinded, independent assessment of 
photographs at post-treatment Day 90 compared to baseline. Lift is concluded if at least 
two of three independent, blinded evaluators report “eyebrow lift” in the Day 90 
standardized, photographic images when compared to baseline photographic images. 
Secondary effectiveness evaluations will include a qualitative assessment of improvement 
in eyebrow lift at Day 180, as well as Day 90 and Day 180 evaluations of quantitative 
measurement of eyebrow lift and change from baseline in three FACE-Q modules (i.e., 
Satisfaction with Forehead and Eyebrows, Satisfaction with Lower Face and Jawline, and 
Patient-perceived Age VAS). 
Standard safety evaluations, including the incidence of AEs and SAEs, will be assessed. 
. 
Section 11.1 
 detail a full schedule of study events and a schedule of 
events for each visit. 
8.2 
Discussion of Study Design, Including the Choice of Control Groups 
As detailed in Section 8.1, this is a 180-day, prospective, evaluator-blind, multicenter, 
staged, confirmatory study designed to evaluate the safety and effectiveness of the Octave 
System in lifting the eyebrow and improving the appearance of the face and neck. 
The 90-day minimum study duration represents a reasonable timeframe to assess 
effectiveness, as well as longer-term safety.[12, 15, 16] The multicenter design approach 
will increase the representativeness of study results and decrease site-related biases. 
Treatment guidelines in the current protocol (Section 10.5.1.3) follow those used for 
clearance of eyebrow lift on the Ulthera DeepSEE System 
 
Lastly, all enrolled subjects will receive treatment, and no control group is planned. 
However, following guidance provided by the FDA and to reduce potential bias associated 
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with using only treated subjects’ photos for evaluation, paired photographs of 
approximately 25 untreated individuals, collected at two time points by the central 
photography vendor (Section 11.2.1.1.1), will be randomly distributed among the pre- and 
post-treatment paired photos of treated subjects, and all will be presented to the blinded, 
independent photographic evaluators (Section 11.2.1.1). 

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9 STUDY POPULATION AND RESTRICTIONS 
9.1 
Number of Subjects and Sites 
Approximately 40 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 
60 subjects will be screened; assuming attrition of 10 subjects, 
approximately 50 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: 5 sites) in the United States, while all other subjects will be enrolled in Stage 2. 
The number of investigational sites will not exceed five in total. During Stage 1, safety 
data collected to Day 14 will be evaluated. All subjects enrolled in Stage 1 will participate 
until study end at Day 90 or Day 180 if reconsented for extended participation. In Stage 2, 
all other enrolled subjects will participate for a maximum duration of 180 days (± 14 days). 
Both males and females and all FST are eligible for study participation. In addition, 
approximately 15% of the enrolled subjects will be categorized as FST IV, V, or VI, and 
of which approximately 7.5% will be categorized as FST V or VI. 
Subjects who are enrolled and who do not complete the study will not be replaced. Day 180 
endpoints will only be assessed among subjects who consent for 180-day study duration or 
reconsent at Day 90 for extended study participation. 
Photographs of approximately 25 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 Criteria #3 and #4 in Section 9.2.1), the Octave System’s supplemental imaging 
mode will be used 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.[14] 
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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9.2.1 
Inclusion Criteria 
To be eligible for study participation, the treating investigator will ensure each subject 
meets all study inclusion criteria at the screening (Scr) and/or baseline (BL) visit as 
follows: 
Inclusion criteria 
Scr 
BL 
1.
Healthy male or female aged 35 to 65 years at the time of screening.
X 
2.
Mild to moderate eyebrow/upper-face laxity that is amenable to improvement
with non-invasive intervention and is not severe enough for surgical
intervention.
X 
3.
Mild to moderate fine lines, wrinkles, and laxity of the face and neck that are
amenable to improvement with non-invasive intervention and are not severe
enough for surgical intervention.
X 
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9.2.2 
Exclusion Criteria 
Subjects meeting any of the following criteria at the screening (Scr) and/or baseline (BL) 
visit are not eligible to participate in the study: 
Exclusion criteria 
Scr 
BL 
 Presence of an active systemic or local skin disease that may affect wound 
healing. 
X 
X 
 Scarring in area(s) to be treated. 
X 
X 
. Active implants (e.g., pacemakers or defibrillators), ports, or metallic implants 
in area(s) to be treated. 
X 
X 
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Exclusion criteria 
Scr 
BL 
 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. 
X 
X 
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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 where a subject is not meeting eligibility criteria due 
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 
Investigators will be instructed to immediately pause subject treatment upon the rare 
occurrence of an intra-procedural adverse event of interest, such as:  
1. Second-degree burn/blister; 
2. Neurological change, including, for example: 
o Motor (paralysis/weakness/paresis/twitching); or 
o Sensory (changes in vision, hearing, tinnitus). 
Additional information, including stopping rules, are described in Section 9.2.8. 
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. 

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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. 
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 and 
), 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 
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every attempt to follow all 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 
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. 

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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 investigationa l-
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. 
In the case of an investigator-reported adverse event of interest (AEI; see Section 12.7), a 
root-cause investigation will be conducted to determine the cause of the event, the outcome 
of the event, and the status of subject. The investigator and Merz will conduct a thorough 
evaluation of the event. Concurrent to the root-cause investigation, the study’s DMC may 
be convened for an Exceptional Meeting to review the event and findings from the root-
cause investigation. Based on input from the DMC, if applicable, and Merz’s investigation, 
Merz will determine if the study should be suspended. 
Investigator reporting of specific treatment-related AEIs resulting in immediate study 
suspension and FDA notification within seven (7) working days of receipt is as follows: 
− Second-degree burn, regardless of duration. 
− Neurological change that presents or persists after the anesthetic effect has dissipated, 
including, but not limited to: 
o Motor effects manifesting as muscle paralysis, muscle weakness, paresis, muscle 
twitching, eyelid ptosis, or facial asymmetry; 
o Sensory effects manifesting as numbness, paresthesia, any visual change, any 
auditory change, skin tingling, skin burning, or prolonged pain (> 1 week); or 
o Sympathetic/parasympathetic 
effects manifesting 
as reduced or increased 
perspiration or eye dryness. 
− Volume loss/atrophy/depression of skin – at any time. 
Further, the study will be stopped if > 5% of treated subjects experience any scar, atrophy 
(deep or superficial), burn with sequelae lasting > 14 days, or other visible or palpable 
damage. 
Additional reasons for suspension or premature termination of the study include, but are 
not limited to: 
• Determination of a potential safety risk to subjects; 

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• 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. 
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 and 
). 
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 STUDY DEVICE AND TREATMENT OF SUBJECTS 
10.1 Description of Study Device 
The Octave System is the second-generation Ulthera platform technology. The new Octave 
System is to be marketed for similar intended uses and indications for use as the cleared 
DeepSEE System (Ulthera System K180623; originally launched in the US in 2009), 
namely for non-invasive dermatological aesthetic treatment to lift the eyebrow and improve 
the appearance of the face and neck. 
 
 The Octave System 
consists of four primary components (console, handpiece, transducers, and cart) that allow 
the user to visualize and precisely deliver therapeutic heat to select tissue layers within the 
skin using microfocused ultrasound. 
A variety of transducer designs is available at different frequencies and nominal treatment 
depths 
 
 
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Reference the current IFU 
 for additional information related to the Octave 
System’s technological characteristics. 
10.1.1 
Mechanism of Action 
10.1.2 
Operating Information 
 the user interface displayed during treatment is dominated in the 
center by the ultrasound image. Other control and information panels surrounding the 
ultrasound image enable changes in the energy level, monitor line delivery, track the 
treatment depth, and allow the activation of imaging and storing of ultrasound images. 
 
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When a treatment zone is selected using therapy controls on the touch panel, the energy, 
spacing, and length parameters will be preset to study-specific values. The maximum 
number of TCPs and spacing are fixed and dependent on the specific transducer inserted 
into the handpiece. For this clinical trial, the treating investigator or delegated and qualified 
study personnel will be able to adjust the energy level and the line count, within required 
ranges and per treatment region, according to the investigator’s discretion. 
 
 
 
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10.2 Instructions for Use and Administration 
The investigational device should be used in the brow, face, and neck region in accordance 
with the information presented in Section 10.5. Additional information on product usage 
is provided in the current version of the Octave Clinical IFU 
 
The Octave System should not be used on a subject’s eye(s) or in a location or technique 
where ultrasound energy can reach the eye. It is recommended that the following areas be 
avoided during treatment with the Octave System: 
• Thyroid gland, thyroid cartilage, and trachea; 
• Major vessels; and 
• Major sensory and motor nerves of the face. 
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. 
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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. 
Each subject will receive a unique subject number upon entry in the EDC system. In cases 
when subjects are not eligible for enrollment at the baseline visit (e.g., due to a temporary 
condition), they will be considered a screen failure. Rescreening of such a subject is 
allowed upon resolution of the temporary condition. In this case, a new subject number 
will be assigned, and all screening assessments will be repeated. 
All subjects will receive a single Ultherapy treatment on the Octave System – that is, no 
randomization will be used. 
10.5 Study Treatment 
All protocol-specific criteria for the administration of study treatment must be met and 
documented prior to the start of any study treatment. All treatments with the investigationa l 
device will be performed on site by the treating investigator or by delegated and qualified 
study personnel. Subjects will 
not be dispensed any investigational 
material. 
Any noncompliant subject or site may be discontinued from the study (Section 9.2.6.2 and 
Section 9.2.7, respectively). 
10.5.1 
Planned Treatment Procedure and Administration 
Subjects in Stage 1 will be enrolled to receive treatment of the brow, upper, mid, and lower 
face, and neck with one transducer beginning at energy level 4 
 
 and one transducer beginning at energy level 2 
 
Subjects in Stage 2 will be enrolled to receive treatment of the brow, upper, mid, and lower 
face, and neck with three transducers beginning at energy level 4 
 
and one transducer 
beginning at energy level 2 
 In both stages, energy 
levels can be titrated down at the investigator’s discretion. 
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10.5.1.1 
Pre-Treatment Assessments 
All subject-related, pre-treatment study activities (Section 11.1) should be completed prior 
to administration of pre-treatment medications. 
10.5.1.2 
Pre-Treatment Medications and Procedure 
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10.5.1.3 
Treatment Region and Administration Procedure 
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10.5.1.3.2 
Stage 1 Treatment 
For Stage 1, treatment lines should be administered with the 
 transducers first, 
followed by the 
 transducer. Treatment with the 
 transducer should begin 
at energy level 4 
 and titrated down to energy level 1 
 
at the investigator’s discretion. Treatment with the shallow transducer 
 should begin at energy level 2 
 and can be reduced to energy level 1 
(i.e., 0.15 J), at the investigator’s discretion. 
At the investigator’s discretion, a line-count range, per treatment zone, is allowed 
 Each zone must receive at least the minimum number of lines and should not 
receive more than the maximum number of lines. The investigator will perform an 
ultrasound scan prior to treatment to determine the presence of soft tissue at the appropriate 
depth for the intended transducer(s) to be used within each region, according to Inclusion 
Criteria 4 and 5; the investigator will then record the intended treatment plan on the 
treatment planning worksheet. Study subjects administered line counts that differ by ± 10% 
of the treatment guideline will be categorized as receiving a full treatment and will not be 
considered protocol deviations 
 
To ensure appropriate collection of pain data 
, each treatment zone should 
receive the full line count with each transducer 
 before moving to the next zone. 
Laterality is the subject’s right or left. 
Investigators will be trained by the sponsor to use Octave System ultrasound imaging to 
ensure proper treatment is delivered (e.g., contact, depth). 
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10.5.1.3.3 
Stage 2 Treatment 
Stage 2 will not be performed until confirmation is received from FDA that the 
 
transducers may be used. 
For Stage 2, treatment lines should be administered with the 
transducers first, 
followed by treatment with 
 transducer, and lastly with the 
 transducer. 
Treatment with the three deeper transducers 
 
should begin at energy level 4 
 
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. At the investigator’s discretion, each transducer’s energy setting can be titrated 
down to energy level 1 
 
. Treatment with the shallow transducer 
 should begin at energy 
level 2 
 and can be reduced to energy level 1 
 at the investigator’s 
discretion. 
At the investigator’s discretion, a line-count range, per treatment zone, is allowed 
 Each zone must receive at least the minimum number of lines and should not 
receive more than the maximum number of lines. The investigator will perform an 
ultrasound scan prior to treatment to determine the presence of soft tissue at the appropriate 
depth for the intended transducer(s) to be used within each region, according to Inclusion 
Criteria 4 and 5; the investigator will then record the intended treatment plan on the 
treatment planning worksheet. Study subjects administered line counts that differ by ± 10% 
of the treatment guideline will be categorized as receiving a full treatment and will not be 
considered protocol deviations 
 
To ensure appropriate collection of pain data 
 each treatment zone should 
receive the full line count with each transducer 
 before moving to the next zone. 
Laterality is the subject’s right or left. 
Investigators will be trained by the sponsor to use Octave System ultrasound imaging to 
ensure proper treatment is delivered (e.g., contact, depth). 
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Laterality is the subject’s right or left. 
Treatment should begin with the deepest transducer set initially to energy level 4, except for the 
transducer which should start at energy level 2; additional pain medication (Section 10.5.1.2), as well 
as incremental reduction in energy, is allowed, as necessary, for subject comfort. 
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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 mild to moderate 
eyebrow/upper-face laxity and mild to moderate fine lines, wrinkles, and laxity of the face 
and neck will receive a single Octave-Ultherapy treatment of the full face and neck 
according to the treatment guidelines presented in Section 10.5.1.3. No additional 
treatments will be offered under this study protocol. 
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10.5.3 
Treatment Interruption and Modification 
If any problems occur during system operation, the treating clinician 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 
diseases, previous aesthetic treatments) should be documented in the eCRF.
 
 
 
10.7 Study Supplies and Packaging of Treatment Supplies 
Sites will be supplied with the Ulthera Octave System, including console, handpiece, 
transducers, and cart. This investigational medical device (IMD) is to be used exclusively 
for treatment of subjects enrolled in this study and will be labeled as follows: “CAUTION 
- Investigational Device. Limited by Federal (or United States) Law to Investigational 
Use.” Device labels will also note the manufacturer name and address and the quantity 
within the package. An IFU 
 will be provided with each system. 
Sites will also be supplied with study-specific ultrasound gel, cleanser for washing of the 
treatment area, and a handheld mirror. 
10.8 Receipt, Storage, Dispensing, and Return/Disposal 
Upon receipt, study personnel will verify the contents of all study supplies received and 
promptly notify the sponsor of any discrepancies or damages. The investigator or designee 
will keep a record of the study-product delivery to the study site. 
All study devices must be stored in a secure area. 
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Only authorized study personnel may administer pain medication and study treatment, and 
only subjects enrolled in the study may receive the investigational 
treatment. 
The investigator is responsible for maintaining a current, accurate record of all study-
treatment dispensation. 
At the end of the study and after verification of study-equipment accountability, it is the 
investigator’s responsibility to return all unused and used IMD equipment (i.e., console, 
handpiece, transducers, and cart) to the sponsor. Appropriate records of return must be 
maintained for accountability purposes. 
All study-accountability procedures must be completed before the study is considered 
complete. 
10.9 Device Accountability Procedures 
Accountability for study supplies at the investigational site is the responsibility of the 
investigator. Access to the IMD will be controlled, and the IMD will be used only in the 
clinical investigation and according to the clinical study protocol. The sponsor will keep 
records to document the physical location of all IMDs from shipment to the investigationa l 
sites until return to the sponsor. The investigator or an authorized designee is responsible 
for ensuring that accurate records of receipt, use and return 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 
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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 to Day 14, and subjects will participate until study end at 
Day 90 or Day 180 if reconsented for extended participation. In Stage 2, all enrolled 
subjects will participate for a maximum duration of 180 days (± 14 days). The planned 
duration of participation for individual subjects is up to 30 weeks, including up to 21 days 
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11 STUDY PROCEDURES 
11.1 Visit Schedule 
The investigation activities and visit schedule are detailed in the Schedule of Events 
 
The purpose of the screening visit (Visit 1) is to determine subject eligibility for study 
participation and must be completed no more than 21 days prior to Day 1 (Visit 2). 
Informed consent is to be obtained at the screening visit, and the reviewing/recording of 
AEs begins upon ICF signature. Subject demographics, including FST 
 
should be recorded in the eCRF, and a subject-reported medical history is acceptable. 
Note: Additionally, for each site, approximately the first four to five subjects with mild to 
moderate brow and upper face laxity, as well as mid- to lower face and/or submental fine 
lines, wrinkles, and laxity, as enrolled by the investigator, will be confirmed for study-
appropriate findings via an independent photographic reviewer. 
In addition to the activities listed in the Schedule of Events 
 
• At Visit 2 (Day 1), prior to performing the investigator’s skin examination, the subject 
must wash the treatment area to remove any moisturizers/emollients, makeup, bronzing 
agents, etc. on the face and/or neck region, if necessary. 
• 
 
 
• At Visit 3, Stage 1 subjects will be requested to reconsent for extended study 
participation to 180 days. If reconsented, study personnel should schedule follow-up 
Day 120 and Day 150 phone call(s) and Visit 4. 
• All required subject-related, pre-treatment procedures and assessments should be 
completed before the administration of oral or IM pain medication (Section 10.5.1.2). 
• After administration of the pain medication, study personnel should verify all study-
specific treatment settings on the Octave System and prepare study-specific materials 
needed for treatment (e.g., ultrasound gel). Study personnel should prepare inhaled 
nitrous oxide/oxygen mixture for potential use, if available. 
All subjects will receive a single, site-administered Ultherapy treatment using the Octave 
System (Section 10.5.1.3) on Day 1 (Visit 2). Subject-reported pain associated with 
treatment will be assessed after completing treatment with each transducer and for each 
region treated (Section 11.2.2.2.3). Importantly, 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-
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specific options to control pain (Section 10.5.1.2). Due to pre-treatment and intra-
procedural medications, subjects must have a driver following the study treatment visit 
(Section 10.5.1.2). 
Subjects will be contacted by telephone 3, 14, 28, 120, and 150 days after treatment and 
will be required to present for an unscheduled visit if indicated by safety concerns.
 
 
 
 
Safety follow-up will occur until 
Day 90 ± 7 days or Day 180 ± 14 days for subjects who reconsent, when applicable, for 
extended participation. 
The primary endpoint visit will occur at Visit 3 (Day 90 ± 7 days). Prior to the investigator’s 
skin examination, 
the subject must wash the treatment area to remove any 
moisturizers/emollients, makeup, bronzing agents, etc. on the face and/or neck region, if 
necessary.
 
 
 
In all cases, even those in which a subject prematurely discontinues the study, a final 
assessment 
 should be 
performed. 
11.1.1 
Scheduled Visits 
All scheduled visits and applicable study assessments must occur as noted in Section  11.1 
 
11.1.2 
Unscheduled Visits 
To ensure subject safety, any subject who, for any reason, requires additional follow-up 
that does not coincide with a scheduled study visit should have that visit recorded as an 
unscheduled visit, during which concomitant medication/procedures, skin examination, 
and AEs must be assessed and recorded. 
 
 
An unscheduled visit must be scheduled if information acquired from a subject during a 
post-treatment phone call requires additional follow-up, as determined by the investigator. 
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11.2 Study Assessments and Definitions 
11.2.1 
Effectiveness Assessments 
The effectiveness of the Octave System to lift the eyebrow and improve the appearance of 
the face and neck will be evaluated using several methods, including qualitative assessment 
of photographs by three blinded evaluators, quantitative measurement of eyebrow lift, and 
three FACE-Q assessments (i.e., Satisfaction with Forehead and Eyebrows, Satisfaction 
with Lower Face and Jawline, and Patient-perceived Age VAS). 
Refer to the respective endpoints (Section 7.2) and visit schedules (Section 11.1 and 
 for additional information on the effectiveness assessments. 
11.2.1.1 
Standardized 2D Photographs 
For assessment of the primary effectiveness endpoint, standardized 2D photographs will 
be taken at the screening visit and at Day 90, at a minimum. Among reconsented Stage 1 
subjects and all Stage 2 subjects, additional standardized 2D photographs will be taken at 
Day 180. Frontal and oblique views of the face and neck are to be obtained using the 
camera system provided, paired with the Canfield IntelliStudio platform to standardize 
image capture. Standardized 2D photographs will be utilized to complete the independent 
photographic review (Section 11.2.1.1.2), the quantitative eyebrow lift measurement 
(Section 11.2.1.2.1), 
 
Since photographs are of critical importance as a reference measure throughout the study, 
the 2D photographs taken at the screening visit (Visit 1) will be reviewed and accepted by 
the central photography vendor prior to treatment. If a subject’s screening photographs are 
deemed unsatisfactory by the central photography vendor, photographs will be retaken at 
Visit 2. Any additional photographs collected at Visit 2 must be collected prior to treatment 
administration. If repeat photography is needed, the Visit 2 (pre-treatment) photographs 
will default to the baseline photographs and will be used for reference throughout the study. 
If no repeat photography is needed, the screening photographs will default to the baseline 
(pre-treatment) photographs and will be used for reference throughout the study. 
At each site, the respective study photographers must be trained in taking standardized 
photographs and follow the instructions provided in a separate photography user manual. 
It is of the utmost importance that subjects are photographed in highly standardized 
positions and with the same setup (i.e., standardized distance, area, views, color standard, 
lighting, and background). Every effort should be made to have the same trained study 
personnel take photographs at every visit, and to maintain the setup of the photo studio 
over the course of the study, with the identical and exact fixed camera positions for the 
different views and light setups. 
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11.2.1.1.1 
Photographs of Untreated Individuals 
Photographs of approximately 25 untreated individuals will also be prepared, providing a 
subset of untreated photographs for assessment by the blinded evaluators. 
After removing any moisturizers/emollients, makeup, bronzing agents, etc. on the face 
and/or neck region, these untreated individuals will be required to meet selected appearance 
criteria as follows: 
• Male or female aged 35 to 65 years. 
• Mild to moderate eyebrow/upper-face laxity and fine lines, wrinkles, and laxity of the 
face and neck that are amenable to improvement with non-invasive intervention and 
are not severe enough for surgical intervention. 
• No scarring in the facial or neck area. 
• No tattoos in the facial or neck area. 
• No open wounds or lesions in the facial or neck area. 
• No active, cystic, or severe inflammatory acne in the facial or neck area. 
• Body mass index (BMI) below 28. 
• No facial hair (i.e., beard, sideburns, etc.) that would interfere with study assessments 
and/or create inconsistency in required study photography. 
• No evidence of recent excessive or prolonged exposure to sunlight, tanning booths, sun 
lamps, or UV-light sources in the facial or neck area. 
• No evidence of recent use of pigmenting 
agents (e.g., self-tanning agents, 
bleaching/depigmenting agents) in the facial or neck area. 
• No evidence of recent medical procedures in the facial or neck area. 
• 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 dental, face, or neck procedure or treatment until after 
the second photo is taken. 
• No obvious facial asymmetry, ptosis, excessive dermatochalasis, deep dermal scarring, 
or thick sebaceous skin. 
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 

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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. 
11.2.1.1.2 
Photographs for Independent, Blinded Evaluation 
To assess the proportion of treated subjects with eyebrow lift 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 frontal and oblique views, 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). 
Image sets will be randomly distributed for presentation to the blinded evaluators. 
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). The blinded evaluators will be informed that the photographs for review will 
include both treated subjects and untreated individuals. However, they will not be informed 
of the ratio of untreated to treated subjects, nor will they be informed of how many subjects 
are treated/untreated. 
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 appearance of the eyebrow observed in the comparator Photograph 2: 
Eyebrow Lift or No Eyebrow Lift?”. 
Lift will be declared if at least two blinded evaluators indicate “Eyebrow Lift” for the 
comparator photograph. 

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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. 
11.2.1.2 
Secondary Effectiveness Assessments 
11.2.1.2.1 
Quantitative Assessment of Eyebrow Lift 
Treatment-related lift in eyebrow position on frontal view will be measured by calculating 
the differences in eyebrow height using baseline and Day 90 and Day 180 images. 
Responders will be defined as subjects achieving ≥ 0.5 mm lift in eyebrow position. 
Standard images of the subject’s face will be collected before treatment and at Day 90 and 
at Day 180 to visualize and quantify changes in the treated regions (Section 11.2.1.1). 
Canfield Capture software and a Canfield 2D digital photography system will be used for 
image collection, storage, and analysis. To ensure consistent, reproducible study photos 
from baseline to Days 90 and 180, photography procedures, including camera and lighting 
set-up requirements, will be described in a separate photography user manual. 
To evaluate the change in eyebrow position, quantitative estimates will be measured in 
reference to an anatomical line connecting two (fixed) bony points on the face (medial 
canthi) and subsequently measuring the perpendicular distance from this line to the rim of 
the eyebrow at multiple points (Appendix 16.3). Utilizing the frontal photographic view, 
quantitative results will be calculated using five evenly spaced points on the brow. 
Height will be calculated at each of the five points and subsequently averaged to generate 
the average eyebrow height (AEH). (Note: MEH = maximum eyebrow height) Eyebrow 
lift will be indicated by the calculated change (delta) between baseline and Day 90 and 
Day 180 height of the brow. 
Additional information on the methodological plan, detailing photograph collection 
through quantitative measurement, will be provided in a supporting document, developed 
collaboratively between the sponsor and the 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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Beginning after treatment on Day 1 (Visit 2), subjects will be asked to record daily, for 28 
days, the following: 
• The presence/absence and intensity (mild, moderate, severe) of any pre-defined 
CTRs (Table 9) and 
• Any other sign or symptom the subject experiences that is not already listed in the 
eDiary. 
All CTRs are expected to be mild and transient in nature. Any CTR that is more severe 
than expected and/or is not resolving within the expected amount of time (Table 9) should 
be evaluated by the investigator as a possible AE or SAE and reported accordingly. The 
treating investigators will acknowledge their review of each subject’s eDiary and determine 
if any entries should also be documented and reported as AEs. Reports of any safety 
concerns by telephone should be escalated to an unscheduled site visit (Section 11.1.2), at 
the discretion of the treating investigator. 
A CTR that has not resolved and is still ongoing upon completion of the diary shall be 
recorded as an AE by the investigator. Subjects can also report any unforeseen/ 
unanticipated events (i.e., as free text) in the eDiary. Any event recorded by the subject 
that is not predefined shall be recorded as an AE by the investigator except if the additional 
event is already covered by a pre-defined CTR and does not describe a new event. 
Additional information is provided in Section 12.8. 
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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; 
• Urine pregnancy tests (only if subject is of childbearing potential); 
• Types of transducers used in each treatment region; 
• Number of treatment lines administered, stratified by treatment region and transducer; 
• Energy level(s) used, stratified by both treatment region and transducer; 
• Relevant medical history/concomitant diseases; and 
• Concomitant therapies. 
11.2.4 
Appropriateness of Assessments 
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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; 
• AE of Interest (yes or no); 
• 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 

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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; 
Section 12.4). 
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 disease; 
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 
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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. 
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; 

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• An identifiable reporting source (investigator/study site identification); and/or 
• An event or outcome that can be identified as serious. 
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 and to Total Clinical Trial 
Management (TCTM) via the email addresses provided below: 
Merz North America, Inc. Product Safety 
6501 Six Forks Road 
Raleigh, NC 27615 
US 
Merz Product Safety Email: AxUS-adverse.events@merz.com 
TCTM Email: octavesae@totalcro.com 
12.3 Definition of an Adverse Device Effect (ADE) 
An ADE is defined as an AE related to the use of an IMD. 
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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. 
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 
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Note: The term “technical complaint” is synonymous with the term “device deficiency”. 
The term device deficiency is used in this study. 
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. 
12.7 Adverse Events of Interest (AEI) 
Adverse events of interest are serious or non-serious AEs that have special importance for 
this product or program. The alert terms, as noted below, are events that Merz wishes to 
monitor more closely throughout the study. These events will have onset on or after date 
of first administration of study treatment and present or persist after the anesthetic effect 
has dissipated. The investigator will be instructed to report any AE of interest immediately 

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(no later than 24 hours of awareness) to Merz using the Adverse Event of Interest Form. 
This form should be submitted to the contacts referenced in Section 12.2.2. 
Adverse events of interest include, but are not limited to the following: 
− Neurological motor events1; 
− Neurological sensory events2; 
− Neurological sympathetic or parasympathetic events3; 
− Any burn; 
− Any scar; 
− Any atrophy (deep or superficial)4; or 
− Any other visible or palpable damage. 
1 Examples include muscle paralysis, muscle weakness, paresis, muscle twitching, eyelid ptosis, or facial 
asymmetry. 
2 Examples include numbness, paresthesia, any visual change, any auditory change, skin tingling, skin 
burning, or prolonged pain (> 1 week). 
3 Examples include reduced or increased perspiration or eye dryness. 
4 An example includes volume loss. 
12.9 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 
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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 72% is assumed for the proportion of subjects with eyebrow lift 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 in the previous 
Ulthera System eyebrow clearance study 
 Monte-Carlo simulations were 
conducted to obtain sample sizes of evaluable subjects required to achieve an improvement 
rate (i.e., eyebrow lift reported by two of three independent, blinded evaluators) of ≥ 65% 
and lower bound of 1-sided 95% confidence interval above 50%. To achieve this threshold 
with ≥ 85% power, a sample size of 40 evaluable subjects will be required. Assuming a 
maximum attrition of 10 subjects, approximately 50 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 40 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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13.4 Analysis of Study Data 
Adequate descriptive statistics will be provided for each effectiveness and safety evaluation 
as provided in Section 7.2. Numeric variables will be summarized by number of 
observations, mean, standard deviation, min, median, max (i.e., metric statistics). 
Categorical variables will be summarized by frequencies and percentages per category 
where the denominator will be chosen according to the adequate analysis population 
(i.e., frequency statistics). Ordered categorical data will be summarized by quantitative and 
frequency statistics. Variables will be analyzed as absolute data and as change from 
baseline, as applicable. Shift tables, confidence limits (95%, two-sided), and descriptive  
p-values will be given, where appropriate. 
All data captured in the eCRF will be listed. 
13.4.1 
Effectiveness Analyses 
Unless otherwise specified, all effectiveness endpoints will be summarized for the ITT 
population. 
13.4.1.1 
Primary Effectiveness Endpoint 
The proportion of subjects fulfilling the primary endpoint will be described by frequency 
statistics for the ITT subset. 
Effectiveness is established if the point estimate is ≥ 65% and the lower bound of the      
one-sided 95% Wilson CI is > 50%. 
In addition, the proportion of untreated individuals fulfilling the primary endpoint will be 
calculated. It is expected that the point estimate for the proportion of untreated individua ls 
is < 50%. 
Sensitivity analyses will comprise: 
• PP population with observed cases, 
• ITT with observed cases, and 
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• ITT with missing value treated as no eyebrow lift. 
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 Endpoints 
13.4.1.2.1 
Independent Photographic Review for Eyebrow Lift at Day 180 
Note: Secondary endpoint will be assessed among Stage 1 subjects who reconsent for 
extended study participation and all Stage 2 subjects. 
The proportion of subjects fulfilling the qualitative eyebrow lift secondary endpoint will 
be described by frequency statistics for the ITT subset, including the one-sided 95% Wilson 
CI. 
13.4.1.2.2 
Quantitative Eyebrow Lift 
To quantitatively assess eyebrow lift from baseline to Day 90 and Day 180, the proportion 
of responders, defined as subjects achieving ≥ 0.5 mm eyebrow lift at Day 90 and Day 180 
compared to baseline, will be described by frequency statistics. Success for the quantitative 
eyebrow lift will be established if the lower bound of the one-sided 95% Wilson CI for 
proportion of responders is > 50%. Additionally, time course of absolute values and change 
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from baseline in mm will be described by metric statistics. These analyses will be provided 
by facial side (left/right) and overall. For the overall analysis, a subject will be responder 
if ≥ 0.5 mm eyebrow lift for both sides is achieved, while metric statistics will be based on 
the average of the right and left sides on frontal view. 
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13.4.2 
Safety Analyses 
All safety evaluations will be summarized for observed values in the SP. 
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. 
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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. 
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. 
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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. 
13.5 Special Statistical/Analytical Issues 
13.5.1 
Subject Discontinuation and Missing Data 
The methods intended for handling a missing primary or select secondary effectiveness 
endpoint are described in Section 13.4.1.1 and Section 13.4.1.2.1, respectively. 
Handling of missing scores of FACE-Q modules are described in Section 13.4.1.2.3. 
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 and treated with the 
 
 transducers. An interim database close and interim safety analysis through Day 14 
will be conducted for Stage 1 subjects. 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 Day 14 safety data from 
Stage 1 subjects. At the conclusion of the safety assessment for Stage 1, expansion to using 
the 
 transducer may be considered based on the totality of information available 
from this safety data, MDR analysis, and the mitigation measures/strategies proposed for 
this IDE based from the MDR analysis. All Stage 1 subjects will participate until study end 
at 90 days (± 7 days) or 180 days (± 14 days) if reconsented for extended participation. 
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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13.5.3 
Data Monitoring Committee 
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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. 
As noted in Section 13.5.3, a DMC will be convened, and their charter will be established 
in a separate document. 
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). 

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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. 
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 Stage 1 safety analysis 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. 
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. 
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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. 
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 data management 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; 
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• 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; 
• 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. 

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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 
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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15 REFERENCES 
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16 APPENDICES