Clinical trial NCT03510598
Conditions: Body Fat Disorder
Sponsor: Zeltiq Aesthetics
Start date: 2018-03-27; Completion date: 2018-12-08
Enrollment: 16 participants; Allocation: NA; Intervention model: SEQUENTIAL

Brief summary:
Evaluate the safety and efficacy of subcutaneous fat layer reduction in the submental area using multiple therapeutic tools.

Detailed description:
The Zeltiq CoolSculpting System and the sequential use of the injectable drug Kybella for non-invasive and then minimally invasive fat reduction in the submental area will be evaluated during the study.

Arms: arm 1: CoolSculpting followed by Kybella treatments. Kybella supplied in 2mL vials.
Interventions: intervention 1: The ZELTIQ CoolSculpting System intervention 2: Kybella 20 MG in 2 ML Injection
Intervention descriptions: intervention 1: The CoolSculpting machine will be used to perform the treatments. intervention 2: Injectable drug called KYBELLA® (deoxycholic acid)

Protocol documents:
Prot_SAP_000.pdf: 
Information Cover Page 
 
 
 
Zeltiq Aesthetics Protocol ZA17-005 
 
Fat Reduction in the Submental Area – A Sequential Treatment Approach with 
CoolMini and KYBELLA® 
 
Clinicaltrials.gov Identifier:  NCT03510598 
 
 
Protocol Date:  27 February 2018 
 
 
Protocol Redaction Date:  1 November 2021 
 
 
IRB Approval Date:  9 March October 2018 
 
 


ZELTIQ Aesthetics – Confidential and Proprietary  
 
 
Part Number: 
 Revision:  
Page 1 of 46 
Title: Fat Reduction in the Submental Area – A Sequential Treatment Approach 
with CoolMini and KYBELLA® 
Note: Check with Document Control for current revisions of all referenced documents. 
 
ZELTIQ P/N: 
Protocol Number: ZA17-005 
 
This document and the contents hereof are considered proprietary and confidential information of ZELTIQ Aesthetics, 
Inc.  Disclosure to unauthorized individuals or dissemination, publication or copying is prohibited without prior written consent 
of ZELTIQ. 
 
DC00025 
FAT REDUCTION IN THE SUBMENTAL AREA – A 
SEQUENTIAL TREATMENT APPROACH WITH COOLMINI 
AND KYBELLA® 
Investigational Plan 
 
Sponsor 
ZELTIQ Aesthetics, Inc., An Allergan Affiliate  
4410 Rosewood Dr. 
Pleasanton, CA 94588 
Protocol Number: 
ZA17-005 
Protocol Version: 
Protocol Date: 
 
Product (s) 
1.0 
February 27, 2018 
 
ZELTIQ CoolSculpting® System 
KYBELLA® 
Investigator /  
Co-Investigators: 
 
Study Location:  
 
H. Ray Jalian, MD 
Rebecca Fitzgerald, MD 
 
321 N. Larchmont Blvd. 
Suite 906 
Los Angeles, CA 90004 
Sponsor Contact: 
 
 
Allergan Medical Monitor 
Contact: 
 
Safety Reporting: 
 
 
 
 
 
 
 
            
            
 
 
KYBELLA® 
            
 
KYBELLA GRID®    
 
CoolSculpting CoolMini 
            
            
 


ZELTIQ Aesthetics – Confidential and Proprietary  
 
 
Part Number: 
 Revision: 01 
Page 2 of 46 
Title: Fat Reduction in the Submental Area – A Sequential Treatment Approach 
with CoolMini and KYBELLA® 
 
 
ZELTIQ P/N: 
Protocol Number: ZA17-005 
 
This document and the contents hereof are considered proprietary and confidential information of ZELTIQ Aesthetics, 
Inc.  Disclosure to unauthorized individuals or dissemination, publication or copying is prohibited without prior written consent 
of ZELTIQ. 
 
Summary of Changes to Protocol from Previous Version  
 
ZELTIQ Part 
Number 
Protocol Version 
Date 
CS-300548 
1 
 
N/A 
 
Affected Section 
(s)  
Summary of Revisions Made 
Rationale 
 
N/A 
 
 
N/A 
 
 
 
 


ZELTIQ Aesthetics – Confidential and Proprietary  
 
 
Part Number: 
 Revision: 01 
Page 3 of 46 
Title: Fat Reduction in the Submental Area – A Sequential Treatment Approach 
with CoolMini and KYBELLA® 
 
 
ZELTIQ P/N: 
Protocol Number: ZA17-005 
 
This document and the contents hereof are considered proprietary and confidential information of ZELTIQ Aesthetics, 
Inc.  Disclosure to unauthorized individuals or dissemination, publication or copying is prohibited without prior written consent 
of ZELTIQ. 
 
 
INVESTIGATOR SIGNATURE PAGE 
 
 
 
I agree to: 
 
• Implement and conduct this study diligently and in strict compliance with this 
protocol, GCP, and all applicable laws and regulations. 
 
• Maintain all information supplied by the Sponsor, ZELTIQ Aesthetics, an Allergan 
affiliate, in confidence and, when this information is submitted to an Ethics Committee 
(EC), or another group, it will be submitted with a designation that the material is 
confidential. 
 
I have read this protocol in its entirety and I agree to all aspects. 
 
 
 
________________________         _______________         _______ 
Investigator printed name                 Signature 
 
Date 
 
________________________          _______________ 
_______ 
Co- Investigator printed name          Signature 
 
Date  
 
 
 
 
 
 
 
 
 
 
 
RETURN PAGE TO SPONSOR


ZELTIQ Aesthetics – Confidential and Proprietary  
 
 
Part Number: 
 Revision: 01 
Page 4 of 46 
Title: Fat Reduction in the Submental Area – A Sequential Treatment Approach 
with CoolMini and KYBELLA® 
 
 
ZELTIQ P/N: 
Protocol Number: ZA17-005 
 
This document and the contents hereof are considered proprietary and confidential information of ZELTIQ Aesthetics, 
Inc.  Disclosure to unauthorized individuals or dissemination, publication or copying is prohibited without prior written consent 
of ZELTIQ. 
Table of Contents 
 
 
Protocol Summary ........................................................................................................ 6 
1. 
Introduction ............................................................................................................ 7 
1.1. 
Background ................................................................................................................. 7 
1.2. 
Device and Drug Description ..................................................................................... 8 
1.2.1. 
The Device – CoolSculpting System ................................................................................... 8 
1.2.2. 
The Drug – KYBELLA® ....................................................................................................... 9 
1.3. 
Regulatory Status ...................................................................................................... 11 
2. 
Study Protocol ...................................................................................................... 12 
2.1. 
Design ........................................................................................................................ 12 
2.2. 
Study Duration ........................................................................................................... 12 
2.3. 
Physician Participants .............................................................................................. 12 
2.4. 
Site Requirements ..................................................................................................... 13 
2.5. 
Subject Recruitment ................................................................................................. 13 
2.6. 
Sample Size ............................................................................................................... 13 
2.7. 
Subject Eligibility ...................................................................................................... 13 
2.8. 
Informed Consent ...................................................................................................... 15 
2.9. 
Screening Procedures .............................................................................................. 15 
2.9.1. 
Screening Visit; Required; Week -4 to Day 0 ................................................................... 15 
2.10. 
Study Enrollment ....................................................................................................... 16 
2.11. 
Study Treatment ........................................................................................................ 16 
2.11.1. 
Treatment Visit 1; Required; Day 0 ................................................................................... 16 
2.11.2. 
Treatment Visit 2; Required; 6 Weeks +/- 7 days post Treatment 1 ................................. 18 
2.11.3. 
Treatment Visit 3; Required; 6 Weeks +/- 7 days post Treatment 2 ................................. 18 
2.11.4. 
Treatment Visit 4; Optional; 4 to 7 Weeks post Treatment 3 ............................................ 20 
2.12. 
Follow-up Procedures ............................................................................................... 21 
2.12.1. 
Two-Week Follow-Up (after each treatment of either CoolSculpting or KYBELLA®); 
Required: 2 Weeks (± 3 days) after each treatment visit ................................................................... 21 
2.12.2. 
Final Follow-Up Evaluation; Required: 12 Weeks (± 3 weeks) after final treatment visit . 21 
2.13. 
Assessments ............................................................................................................. 23 
2.13.1. 
Safety Assessments.......................................................................................................... 23 
2.13.2. 
Clinician Evaluation using CR-SMFRS ............................................................................. 24 
2.13.3. 
Photography ...................................................................................................................... 24 
2.13.4. 
Ultrasound Measurements ................................................................................................ 25 
2.13.5. 
Subject Self-Rating Scale (SSRS) .................................................................................... 25 


ZELTIQ Aesthetics – Confidential and Proprietary  
 
 
Part Number: 
 Revision: 01 
Page 5 of 46 
Title: Fat Reduction in the Submental Area – A Sequential Treatment Approach 
with CoolMini and KYBELLA® 
 
 
ZELTIQ P/N: 
Protocol Number: ZA17-005 
 
This document and the contents hereof are considered proprietary and confidential information of ZELTIQ Aesthetics, 
Inc.  Disclosure to unauthorized individuals or dissemination, publication or copying is prohibited without prior written consent 
of ZELTIQ. 
2.14. 
Endpoints ................................................................................................................... 26 
2.14.1. 
Primary Endpoints ............................................................................................................. 26 
2.14.2. 
Secondary Endpoints ........................................................................................................ 26 
2.15. 
Statistical Analysis Plan ........................................................................................... 26 
2.15.1. 
Statistical Methods: Overall Plan ...................................................................................... 26 
2.15.2. 
Analysis Population ........................................................................................................... 27 
2.15.3. 
Endpoint Analysis .............................................................................................................. 27 
2.15.3.1. 
Primary Safety Endpoint:............................................................................................................ 27 
2.15.3.2. 
Primary Efficacy Endpoint: Reduction in CR-Submental Fat Rating Scale .................................. 28 
2.15.3.3. 
Secondary Endpoint: Ultrasound ............................................................................................... 28 
2.15.3.4. 
Secondary Endpoint: Subject Self-Rating Scale .......................................................................... 28 
2.15.3.5. 
Sample Size Requirement ........................................................................................................... 28 
2.16. 
Missing Data Handling .............................................................................................. 28 
2.17. 
Protocol Adherence .................................................................................................. 28 
2.18. 
Adverse Events ......................................................................................................... 29 
3. 
Study Management and Quality Control ............................................................ 36 
3.1. 
Study Data Collection ............................................................................................... 36 
3.2. 
Confidentiality ........................................................................................................... 36 
3.3. 
Investigator Responsibilities ................................................................................... 36 
3.3.1. 
General Responsibilities ................................................................................................... 36 
3.3.2. 
Investigator Records ......................................................................................................... 37 
3.3.3. 
Investigator Reports .......................................................................................................... 38 
3.4. 
Sponsor Responsibilities ......................................................................................... 39 
3.4.1. 
General Responsibilities: .................................................................................................. 39 
3.4.2. 
Training ............................................................................................................................. 39 
3.4.3. 
Site Monitoring .................................................................................................................. 40 
3.4.4. 
Final Report ....................................................................................................................... 41 
3.4.5. 
Trial Registration ............................................................................................................... 41 
4. 
Data Ownership .................................................................................................... 41 
5. 
Publication Policy ................................................................................................ 41 
6. 
Risk/Benefit Analysis ........................................................................................... 41 
6.1. 
Benefits ...................................................................................................................... 42 
6.2. 
Risks ........................................................................................................................... 42 
 
 


ZELTIQ Aesthetics – Confidential and Proprietary  
 
 
Part Number: 
 Revision: 01 
Page 6 of 46 
Title: Fat Reduction in the Submental Area – A Sequential Treatment Approach 
with CoolMini and KYBELLA® 
 
 
ZELTIQ P/N: 
Protocol Number: ZA17-005 
 
This document and the contents hereof are considered proprietary and confidential information of ZELTIQ Aesthetics, 
Inc.  Disclosure to unauthorized individuals or dissemination, publication or copying is prohibited without prior written consent 
of ZELTIQ. 
Protocol Summary 
 
Title 
Fat Reduction in the Submental Area – A Sequential Treatment Approach with 
CoolMini and KYBELLA® 
Design 
Prospective, controlled, open-label interventional study 
Purpose 
Evaluate the safety and efficacy of subcutaneous fat layer reduction in the 
submental area using multiple therapeutic tools 
Enrollment 
Up to twenty (20) subjects 
Clinical Site 
Up to three (3) investigational sites 
Subject 
Population 
Healthy adult men and women with clearly visible fat in the submental area, rated 
a 4 or extreme in the CR-SMFRS, that they wish to have reduced.   
Treatment 
 
 
 
 
Primary 
Endpoint 
• Safety endpoint: incidence of device, drug or procedure-related adverse 
events.   
• Efficacy endpoint:  
1. The reduction, from baseline to final follow-up, of submental fat 
(SMF) as assessed by the proportion of subjects who have at least a 
1-grade improvement on the Clinician Reported-Submental Fat Rating 
Scale (CR-SMFRS), and 
2. The reduction, from baseline to final follow-up, of SMF as assessed 
by the proportion of subjects who have at least a 2-grade 
improvement on the CR-SMFRS. 
Secondary 
Endpoints 
1. Reduction in fat layer thickness, as measured by ultrasound at week 12 
post-final treatment. 
2. Subject satisfaction as assessed by the Subject Self-Rating Scale score.  
Sponsor 
ZELTIQ Aesthetics, Inc., An Allergan Affiliate  
4410 Rosewood Dr. 
Pleasanton, CA 94588 
  


ZELTIQ Aesthetics – Confidential and Proprietary  
 
 
Part Number: 
 Revision: 01 
Page 7 of 46 
Title: Fat Reduction in the Submental Area – A Sequential Treatment Approach 
with CoolMini and KYBELLA® 
 
 
ZELTIQ P/N: 
Protocol Number: ZA17-005 
 
This document and the contents hereof are considered proprietary and confidential information of ZELTIQ Aesthetics, 
Inc.  Disclosure to unauthorized individuals or dissemination, publication or copying is prohibited without prior written consent 
of ZELTIQ. 
1. Introduction  
1.1. 
Background 
 
Fat reduction and body contouring procedures, which include invasive, minimally-
invasive, and non-invasive procedures, have become increasingly popular aesthetic 
procedures. Patients who are obese and do not have specific fat bulges but require 
significant fat reduction to achieve aesthetic results are candidates for invasive and 
minimally-invasive procedures, such as liposuction and laser-assisted liposuction. 
Although effective at reducing fat, these invasive and minimally-invasive procedures 
involve significant patient pain, expense, downtime, and the risks typically associated with 
surgical procedures. As a result, patients who do not require significant fat reduction to 
achieve meaningful aesthetic results typically seek non-invasive fat reduction and body 
contouring procedures to avoid the pain, expense, downtime, and surgical risks associated 
with invasive and minimally-invasive procedures. 
 
ZELTIQ Aesthetics has developed and commercialized a technology to non-invasively 
reduce subcutaneous fat.  The technology utilizes the sensitivity of fat cells to cold injury 
in order to selectively eliminate subcutaneous fat tissue without affecting the skin or other 
surrounding tissues. Termed cryolipolysis, this technology enables a non-invasive 
alternative for subcutaneous fat reduction through cellular apoptosis. The CoolSculpting 
System, which is cleared for use in the United States for fat layer reduction through cold-
assisted lipolysis, has been clinically proven to reduce fat bulges, allowing patients to 
achieve noticeable and measurable aesthetic results without the pain, expense, downtime, 
and risks associated with existing invasive and minimally-invasive procedures.  
 
Allergan commercialized a first in class, injectable drug called KYBELLA® (deoxycholic 
acid), indicated for improvement in the appearance of moderate to severe convexity or 
fullness associated with submental fat in adults.  Administrations are given at intervals of 
no less than 4 weeks until the desired result is achieved, up to a maximum of 6 treatment 
sessions.  The total dose of KYBELLA® administered in each treatment session and the 
overall number of treatments are both tailored to the individual patient based on the 
amount and distribution of SMF as well as the patient’s desired result. This minimally 
invasive procedure is another treatment option for patients looking to reduce the double-
chin appearance.   
 
Both CoolSculpting and KYBELLA® are important treatment options for aesthetically-
minded patients who are interested in reducing submental fat using minimally invasive 
interventions. 
 
The purpose of this study is to evaluate the safety and efficacy of subcutaneous fat 


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Part Number:
 Revision: 01 
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Title: Fat Reduction in the Submental Area – A Sequential Treatment Approach 
with CoolMini and KYBELLA® 
 
 
ZELTIQ P/N: 
Protocol Number: ZA17-005 
 
This document and the contents hereof are considered proprietary and confidential information of ZELTIQ Aesthetics, 
Inc.  Disclosure to unauthorized individuals or dissemination, publication or copying is prohibited without prior written consent 
of ZELTIQ. 
reduction in the submental area in subjects initially with extreme submental fullness 
(Grade 4) based on the Clinician Reported-Submental Fat Rating Scale (CR-SMFRS), 
using sequential treatments of CoolSculpting (with the CoolMini applicator) and 
KYBELLA®. 
 
 
 
 
  
 
In this study, subjects will receive two CoolSculpting treatments sessions each consisting 
of one cooling cycle with CoolMini, spaced 6 weeks apart, followed by at least one and up 
to two (2) KYBELLA® treatment sessions 6 weeks post the final CoolMini treatment, 
spaced 4-7 weeks apart.   
 
After the completion of all treatment visits, subjects will be followed for 12 weeks post-
final treatment.  Safety information will be collected at study visits.  Primary efficacy 
assessment will be evaluated at 12-weeks post-final treatment.   
 
Results from this clinical trial will be used to provide feasibility data on the use of both 
CoolSculpting and KYBELLA® treatments sequentially to improve the treatment 
approach and availability for extreme submental fullness.   
 
1.2. 
Device and Drug Description 
1.2.1. 
The Device – CoolSculpting System 
 
 
 
 
 
 
   
 
 
 
 


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Part Number: 
 Revision: 01 
Page 9 of 46 
Title: Fat Reduction in the Submental Area – A Sequential Treatment Approach 
with CoolMini and KYBELLA® 
 
ZELTIQ P/N: CS-300548 
Protocol Number: ZA17-005 
This document and the contents hereof are considered proprietary and confidential information of ZELTIQ Aesthetics, 
Inc.  Disclosure to unauthorized individuals or dissemination, publication or copying is prohibited without prior written consent 
of ZELTIQ. 
 
Figure 1.  Representative CoolSculpting System control unit. 
 
 
Figure 2:  CoolMini Applicator 
 
1.2.2. 
The Drug – KYBELLA® 
 
 
 
 
 


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Part Number: 
 Revision: 01 
Page 10 of 46 
Title: Fat Reduction in the Submental Area – A Sequential Treatment Approach 
with CoolMini and KYBELLA® 
 
ZELTIQ P/N: 
Protocol Number: ZA17-005 
This document and the contents hereof are considered proprietary and confidential information of ZELTIQ Aesthetics, 
Inc.  Disclosure to unauthorized individuals or dissemination, publication or copying is prohibited without prior written consent 
of ZELTIQ. 
  
 
Figure 3:  Molecular Structure of Synthetic Deoxycholic Acid
Figure 4:  Representative packaging of KYBELLA® 2 mL vials 
 
 
 
 
  Completion of this training is 
to be documented in the study file. 
 
 
 
 


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Part Number: 
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Title: Fat Reduction in the Submental Area – A Sequential Treatment Approach 
with CoolMini and KYBELLA® 
 
 
ZELTIQ P/N: 
Protocol Number: ZA17-005 
 
This document and the contents hereof are considered proprietary and confidential information of ZELTIQ Aesthetics, 
Inc.  Disclosure to unauthorized individuals or dissemination, publication or copying is prohibited without prior written consent 
of ZELTIQ. 
 
• At the discretion of the investigator, topical or local anesthesia (e.g., topical or 
injectable lidocaine preparations without epinephrine, ice) may be applied in the 
planned treatment area and any medications will be recorded on the appropriate 
case report form (CRF). 
 
• 
 
 
 
 A grid, 
specifically developed to be applied to the treatment area to guide the placement of 
injections, will be used.  
 
• For each KYBELLA® injection, the investigator will palpate the treatment area to 
determine the approximate thickness of the targeted SMF and inject KYBELLA® 
into fat tissue at a depth of approximately mid-way into the SMF. 
 
• If at any time resistance is met as the needle is inserted, indicating the possibility 
of contact with fascial or nonfat tissue, the needle will be withdrawn to an 
appropriate depth before the injection is given. 
 
• Upon needle withdrawal, pressure will be applied to each injection site as 
necessary to minimize bleeding; an adhesive dressing may be applied.  Upon 
completion of the injections, the area may be gently massaged. 
 
• At each treatment session, the investigator will determine the number and locations 
of injections.  He or she will evaluate each planned injection location to avoid sites 
for which an injection may not be appropriate (e.g., nodule formation, significant 
residual inflammation, other adverse event that warrants a delay, or lack of SMF). 
 
• 
 
 
Subjects may be discharged from the research facility approximately 30 minutes after 
KYBELLA® is administered, provided it is medically appropriate to do so. 
 
At no time is the dilution of KYBELLA® permitted. 
1.3. 
Regulatory Status 
 
 


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Title: Fat Reduction in the Submental Area – A Sequential Treatment Approach 
with CoolMini and KYBELLA® 
 
 
ZELTIQ P/N: 
Protocol Number: ZA17-005 
 
This document and the contents hereof are considered proprietary and confidential information of ZELTIQ Aesthetics, 
Inc.  Disclosure to unauthorized individuals or dissemination, publication or copying is prohibited without prior written consent 
of ZELTIQ. 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
  
2. Study Protocol 
2.1. 
Design 
Prospective, controlled, open-label, interventional study. 
2.2. 
Study Duration  
Enrollment and follow-up is expected to take up to nine (9) months for each 
subject. 
2.3. 
Physician Participants 
Study investigators must be practicing medical physicians with experience in the 
use of both the CoolSculpting System and KYBELLA® injections. Given the 
importance of assuring consistent ratings, and in consideration of investigational 
site logistics, the same evaluating investigator will perform the CR-SMFRS 
scoring for the same patient through all study visits.  


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Part Number: 
 Revision: 01 
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Title: Fat Reduction in the Submental Area – A Sequential Treatment Approach 
with CoolMini and KYBELLA® 
 
 
ZELTIQ P/N: 
Protocol Number: ZA17-005 
 
This document and the contents hereof are considered proprietary and confidential information of ZELTIQ Aesthetics, 
Inc.  Disclosure to unauthorized individuals or dissemination, publication or copying is prohibited without prior written consent 
of ZELTIQ. 
2.4. 
Site Requirements 
Site investigators must have at least one study coordinator with experience in 
conducting aesthetic research and with sufficient time to conduct the study. 
2.5. 
Subject Recruitment 
Subjects who seek reduction of submental fat will be recruited from the general 
population. 
2.6. 
Sample Size 
A maximum of twenty (20) subjects will be treated at up to three (3) 
investigational sites. 
2.7. 
Subject Eligibility 
To be eligible to participate in the study, subjects must meet all of the inclusion 
criteria and none of the exclusion criteria listed in Table 1. 
Table 1.  Eligibility criteria. 
 
Inclusion Criteria 
a) Male or female subjects > 22 years of age and < 65 years of age. 
b) Women of childbearing potential must have a negative urine pregnancy test result 
at screening and agree to practice adequate contraception. 
c) CR-SMFRS grade of 4 (extreme) as determined by the evaluating investigator at 
screening. 
d) Dissatisfaction with the submental area expressed by the subject as a rating of 0, 1 
or 2 using the Subject Self Rating Scale (SSRS) as determined at Screening visit. 
e) History of stable body weight confirmed by the subject, for at least 6 months prior 
to the first treatment session. 
f) Subject agrees to maintain his/her weight (i.e., within 5%) by not making any 
major changes in their diet or exercise routine during the course of the study.  
g) Subject agrees to forgo any treatment or behavior (e.g., unshaven facial hair) 
during the subject’s participation in the study that may affect the assessments of the 
submental area.  
h) Subject is medically able to undergo the administration of KYBELLA® determined 
after review of the subject’s medical history for which the evaluating investigator 
identifies no clinically significant abnormality.   
i) Subject has read and signed the study written informed consent form. 


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Title: Fat Reduction in the Submental Area – A Sequential Treatment Approach 
with CoolMini and KYBELLA® 
 
 
ZELTIQ P/N: 
Protocol Number: ZA17-005 
 
This document and the contents hereof are considered proprietary and confidential information of ZELTIQ Aesthetics, 
Inc.  Disclosure to unauthorized individuals or dissemination, publication or copying is prohibited without prior written consent 
of ZELTIQ. 
Exclusion Criteria 
a) Body Mass Index ≥40 as determined at screening. 
b) Subject has excessive skin laxity, as determined by the evaluating investigator, in 
the neck or chin area or other anatomical feature (e.g., predominant subplatysmal 
fat, loose skin in the neck or chin area, prominent platysmal bands) for which 
reduction in the submental fat may result in an aesthetically unacceptable outcome. 
c) There is evidence of any cause of enlargement in the submental area (e.g., thyroid 
enlargement, cervical adenopathy) other than localized submental fat.   
d) Subject has a history of trauma associated with the chin or neck areas, which in the 
judgement of the investigator may affect evaluation of safety or efficacy of 
treatment.   
e) Subject has a history of treatment with CoolSculpting or KYBELLA® in the 
intended treatment area or has a history of any intervention to treat submental fat 
(e.g., liposuction, surgery, or lipolytic agents). 
f) Subject has a history of treatment with radiofrequency, micro-focused ultrasound, 
laser procedures, chemical peels, or dermal fillers in the neck or chin area within 12 
months before the first treatment session.   
g) Subject has a history of treatment with botulinum toxin injections in the neck or 
chin area within 6 months before the first treatment session. 
h) Subject has a known history of cryoglobulinemia, cold urticaria, paroxysmal cold 
hemoglobinuria or cold agglutinin disease.   
i) Subject has a known history of Raynaud’s disease, or any known condition with a 
response to cold exposure that limits blood flow to the skin.   
j) Subject has a history of facial nerve paresis or paralysis (such as Bell’s palsy) 
k) Subject has a history or current symptoms of dysphagia. 
l) Subject has a history of prior neck surgery, or prior surgery in the area of intended 
treatment, or implant in or adjacent to the area of intended treatment.  
m) Subject has a history of sensitivity to any components of the KYBELLA® or to 
topical or local anesthetics (e.g., lidocaine, benzocaine, novocaine).   
n) Subject has a history of bleeding disorder or is taking any medication that in the 
investigator’s opinion may increase the subject’s risk of bruising.   
o) Subject is currently taking or has taken diet pills or weight control supplements 
within the past month. 
p) Subject has any dermatological conditions, such as scars in the location of the 
treatment area that may interfere with the treatment or evaluation.   


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Title: Fat Reduction in the Submental Area – A Sequential Treatment Approach 
with CoolMini and KYBELLA® 
 
 
ZELTIQ P/N:
Protocol Number: ZA17-005 
 
This document and the contents hereof are considered proprietary and confidential information of ZELTIQ Aesthetics, 
Inc.  Disclosure to unauthorized individuals or dissemination, publication or copying is prohibited without prior written consent 
of ZELTIQ. 
q) Subject has an active implanted device such as a pacemaker, defibrillator, or drug 
delivery system.   
r) Women of childbearing potential not using a reliable means of contraception.   
s) Subject is unable or unwilling to comply with the study requirements.   
t) Subject has received treatment with an investigational device or agent within 30 
days before the subject’s first treatment session. 
u) Any other condition or laboratory value that would, in the professional opinion of 
the investigator, potentially affect the subject’s response or the integrity of the data 
or would pose an unacceptable risk to the subject.   
 
 
2.8. 
Informed Consent  
Study candidates shall receive an explanation of the study objectives, possible risks and 
benefits of the study, and be given adequate time to read the information included in the 
informed consent document. Candidates will be given an opportunity to ask questions 
about any of the information contained in the informed consent. Candidates must verbally 
acknowledge understanding of the informed consent, and sign the consent form 
accordingly. This form must have prior approval of the Institutional Review Board.  
2.9. 
Screening Procedures 
2.9.1. 
Screening Visit; Required; Week -4 to Day 0 
The subject shall be consented for study participation as described in Section 
2.8.  After the informed consent form is signed, subjects will be screened for 
eligibility.  Each subject will be evaluated to determine that all eligibility 
criteria are met.  The investigator or designee shall complete a brief medical 
history and examine the subject to confirm eligibility for the study. 
 
1. Obtain Subject Self-Rating Scale score. 
2. Obtain height and weight. 
3. Evaluating investigator to assess intended treatment area and determine 
severity of submental fullness based on Clinician Reported-Submental 
Fat Rating Scale (CR-SMFRS).   
a. Subjects must score a 4 (extreme) in order to be enrolled. 
4. Assess oral cavity for current dental infection or evidence of dry mouth.   
5. Assess function of the marginal mandibular nerve (grimace with ability to 
show lower teeth) and hypoglossal nerve (tongue does not deviate upon 
protrusion).   


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Title: Fat Reduction in the Submental Area – A Sequential Treatment Approach 
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ZELTIQ P/N: 
Protocol Number: ZA17-005 
 
This document and the contents hereof are considered proprietary and confidential information of ZELTIQ Aesthetics, 
Inc.  Disclosure to unauthorized individuals or dissemination, publication or copying is prohibited without prior written consent 
of ZELTIQ. 
6. Assess upper neck to rule out enlarged lymph nodes or glands. 
7. Assess for dermatological conditions that may lead to exclusion of the 
subject from the study.   
8. Document subject’s medication use (including over-the-counter 
medications, vitamins and herbs), Fitzpatrick Skin Type, and ethnicity, as 
well as any skin irregularities (e.g. moles, birth marks, scars, 
discoloration).   
9. All female subjects of childbearing potential will be asked to take a 
pregnancy test (urine) prior to being treated. If the subject is pregnant, 
she will be excluded from participation.   
 
Female subjects of childbearing potential will be advised to avoid becoming 
pregnant during the course of the study by agreeing to practice adequate 
contraception, in the judgement of the investigator, during the course of the 
study.  If the subject becomes pregnant during the course of the study, she 
will not be treated subsequently with the study device or drug and she will be 
required to have follow-up photographs and ultrasounds.  She will also be 
asked for information about the pregnancy and the birth of the child.   
 
All subjects will be asked to maintain their weight by not making any major 
changes to their diet or exercise regimen during the course of the study.  If 
the weight change is more than 5% at the final visit, the subjects’ data will be 
excluded from the primary Efficacy analyses. Subjects who do not maintain 
their weight within 5% will continue in the study, however their data will be 
excluded from Efficacy analyses.   
 
Subjects who meet all of the inclusion criteria and none of the exclusion 
criteria shall be eligible to participate in the study and the first treatment will 
be scheduled. 
2.10. 
Study Enrollment 
Study Candidates who sign the informed consent form, meet eligibility criteria and 
undergo initiation of study treatment are considered enrolled. Study treatment initiation is 
defined as the initiation of cold therapy after the placement of the applicator on the 
intended treatment area on the scheduled treatment day. 
2.11. 
Study Treatment 
2.11.1. 
Treatment Visit 1; Required; Day 0  
1. Review inclusion and exclusion criteria.  


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Title: Fat Reduction in the Submental Area – A Sequential Treatment Approach 
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2. Repeat pregnancy test for female subjects of childbearing potential 
(urine).  Exclude subject from participation if the results are positive. 
3. If the subjects meet all of the inclusion criteria and none of the exclusion 
criteria, then proceed with the study treatment. 
4. Obtain weight 
5. Obtain baseline photographs using custom standardized setup and 
settings.   
6. Cleanse the treatment area with isopropyl alcohol. 
7. Mark or outline the intended treatment area.  
8. Measure the fat layer thickness of the intended treatment area with a 
commercially-available ultrasound device using a standardized protocol.   
 
  
 
 
 
 
 
 
 
 
 
 
 
   
 
 
   
 
 
   
 
 
 
 
 
 
 
 
 
   
 
 
 
   
 
 
 
 
 
 
  
 


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The investigator or staff will be present during the treatment to monitor 
the progress.  Treatment may be discontinued due to subject discomfort 
or device malfunction.  The need for post-treatment care is not expected 
for this study.  Subjects will be encouraged to call the study site if they 
experience any unusual effects (e.g., severe discomfort or pain, severe 
and/or prolonged erythema, bruising, swelling, blistering, etc.).  Refer to 
Section 6.2 for a listing of the expected side effects of the procedure.   
2.11.2. 
Treatment Visit 2; Required; 6 Weeks +/- 7 days post Treatment 1 
Six-weeks after CoolSculpting Treatment #1, the same evaluating 
investigator from Screening will evaluate the aesthetic result of 
Treatment #1.  A second CoolSculpting treatment will be performed in 
the submental region to achieve the desired aesthetic effect.  The second 
treatment will be performed following the steps outlined in Section 
2.11.1.   
 
The following evaluations will be performed at the 2nd Treatment Visit prior 
to CoolSculpting treatment #2: 
 
1. Obtain weight. 
2. Clinical assessment of the treatment area for any epidermal, dermal and 
subcutaneous findings (e.g., erythema, bruising, swelling, pigment 
changes) as well as alterations in sensation (e.g., numbness, tingling). 
3. Examine the oral cavity for evidence of dry mouth. 
4. Assess lower face motor nerve function.  
5. Obtain adverse event information. 
6. Photography using the same custom standardized setup and settings as 
the pre-treatment photographs (optional) prior to CoolSculpting treatment 
#2. 
7. Perform CoolSculpting treatment #2 as described in Section 2.11.1  
2.11.3. 
Treatment Visit 3; Required; 6 Weeks +/- 7 days post Treatment 2 
Six-weeks after CoolSculpting Treatment 2, the same evaluating 
investigator will evaluate the aesthetic result of Treatment #2, A 
KYBELLA® treatment will be performed in the associated submental 
region in patients assigned a CR-SMFRS of 3 or 2 to further reduce the 
fat and enhance the aesthetic appearance in the submental region.   
 
The following evaluations will be performed at the 3rd Treatment Visit: 
 


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Title: Fat Reduction in the Submental Area – A Sequential Treatment Approach 
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1. Obtain Subject Self-Rating Scale score. 
2. Obtain weight. 
3. Clinical assessment of the treatment area for any epidermal, dermal and 
subcutaneous findings (e.g., erythema, bruising, swelling, pigment 
changes) as well as alterations in sensation (e.g., numbness, tingling). 
4. Examine the oral cavity for evidence of dry mouth. 
5. Assess lower face motor nerve function.  
6. Obtain adverse event information. 
7. Photography using the same custom standardized setup and settings as 
the pre-treatment photographs. 
8. Measure the fat layer thickness of the intended treatment area with a 
commercially-available ultrasound device using a standardized protocol.   
9. Assess intended treatment area and determine severity of submental 
fullness based on CR-SMFRS score at this visit.  Patients who are 
assigned a score of 3 (CR-SMFRS=severe) or 2 (CR- SMFRS=moderate) 
by the evaluating investigator will move on to the KYBELLA® treatment 
phase. 
10. To perform a KYBELLA® treatment:  
 
 
 
 
 
 
a. 
 
 
 
  
 
  
 
 
 
 
 
 
 


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f. 
 
 
 
 
  
 
  
  
i. Immediately post treatment, the treatment site will be examined for 
any epidermal, dermal or subcutaneous findings (e.g., blanching, 
erythema, bruising, swelling); alterations in sensation (e.g., 
numbness, tingling) 
   
j. Obtain adverse event information. 
 
Treatment may be discontinued due to subject discomfort.  The need for 
post-treatment care may include, the optional use of compression 
dressing, icing for pain and local discomfort and hot packs for 
indurations.  Subjects may be discharged from the research facility 
approximately 30 minutes after KYBELLA® is administered, provided it 
is medically appropriate to do so. 
Subjects will be encouraged to call the study site if they experience any 
unusual effects and/or adverse events (e.g., severe discomfort or pain, 
severe and/or prolonged erythema, bruising, swelling, blistering, etc.).  
Refer to Section 6.2 for a listing of the expected side effects of the 
procedure.   
 
2.11.4. 
Treatment Visit 4; Optional; 4 to 7 Weeks post Treatment 3 
Four to seven weeks after Treatment 3 (first treatment with 
KYBELLA®), the same evaluating investigator will evaluate the aesthetic 
result of Treatment #3 (KYBELLA®) and assign a CR-SMFRS score.  
Per the investigator’s discretion and with the subject’s concurrence, 
another KYBELLA® treatment will be performed in the submental region 
in patients assigned a CR-SMFRS <Grade 4 (extreme) to further enhance 
the aesthetic effect.  The KYBELLA® treatment will be performed 
following the steps outlined in Section 2.11.3.   


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The following evaluations will be performed at the 4th Treatment Visit: 
 
1. Obtain weight. 
2. Clinical assessment of the treatment area for any epidermal, dermal and 
subcutaneous findings (e.g., erythema, bruising, swelling, pigment 
changes) as well as alterations in sensation (e.g., numbness, tingling). 
3. Examine the oral cavity for evidence of dry mouth. 
4. Assess lower face motor nerve function.  
5. Obtain adverse event information.  
6. Assess intended treatment area and determine severity of submental 
fullness based on CR-SMFRS score at this visit.  Patients who are 
assigned a score of <4 (extreme) by the evaluating investigator may 
proceed with another KYBELLA® treatment session at this visit. 
7. Photography using the same custom standardized setup and settings as 
the pre-treatment photographs (optional). Perform treatment as described 
in Section 2.11.3 with investigator’s discretion.   
 
2.12. 
Follow-up Procedures  
2.12.1. 
Two-Week Follow-Up (after each treatment of either 
CoolSculpting or KYBELLA®); Required: 2 Weeks (± 3 days) after 
each treatment visit 
The following evaluations will be performed at the 2-week post-treatment 
follow-up visit: 
 
1. Obtain weight. 
2. Clinical assessment of the treatment area for any epidermal, dermal and 
subcutaneous findings (e.g., erythema, bruising, swelling, pigment 
changes) as well as alterations in sensation (e.g., numbness, tingling).  
 
3. Examine the oral cavity for evidence of dry mouth. 
4. Assess lower face motor nerve function. 
5. Obtain adverse event information. 
2.12.2. 
Final Follow-Up Evaluation; Required: 12 Weeks (± 3 weeks) after 
final treatment visit 
The following evaluations will be performed at the final post-treatment 
follow-up visit: 
 


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1. Obtain Subject Self-Rating Scale score. 
2. Obtain weight. 
3. The same evaluating investigator from prior visits will assess treatment 
area and determine severity of submental fullness based on CR-SMFRS 
score at this visit.   
4. Photograph the treatment area using the same custom standardized setup 
and settings as the pre-treatment photographs. 
5. Measure the fat layer thickness of the treatment site with a commercially 
available ultrasound device.   
6. Clinical assessment of the treatment area for any epidermal, dermal and 
subcutaneous findings (e.g., erythema, bruising, swelling, pigment 
changes) as well as alterations in sensation (e.g., numbness, tingling).  
   
7. Examine the oral cavity for evidence of dry mouth. 
8. Assess lower face motor nerve function. 
9. Obtain adverse event information. 
 
Figure 5 illustrates subject enrollment and study flow. Table 2 summarizes the study schedule and 
events at each visit. 
 
 
 
Figure 5. Subject enrollment and study flow. 
 


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Table 2.  Schedule of assessments. 
  
 
Screening 
(< 1 hr) 
Treatment 
Visit 1 
(<  3 hrs) 
Treatment 
Visit 2 
(<  3 hrs) 
Treatment 
Visit 3 
(<  3 hrs) 
Treatment 
Visit 4 
(Optional) 
(<  3 hrs) 
2 Week 
Follow-Up 
(< 1 hr) † 
Final 
Follow-Up 
(< 1 hr) 
Time Frame 
Day  - 30 to 0 
Day 0 
6 ± 1 weeks 
post last tx 
6 ± 1 weeks 
post last tx 
 4-7 weeks 
post last tx 
2 weeks ± 3 
days post each 
tx 
12 ± 3 weeks 
post final tx 
Informed Consent* 
X 
 
 
 
 
 
 
Inclusion/Exclusion 
Criteria 
X 
X 
X 
X 
X 
 
 
Pregnancy Test 
X 
X 
X 
X 
X 
 
 
Medical History 
X 
 
 
 
 
 
 
Tx Site Assessment 
X 
X 
X 
X 
X 
X 
X 
Oral Cavity 
Assessment 
X 
 
X 
X 
X 
X 
X 
Nerve Function 
Assessment 
X 
 
X 
X 
X 
X 
X 
Height 
X 
 
 
 
 
 
 
Weight 
X 
X 
X 
X 
X 
X 
X 
CR-SMFRS 
Assessment 
X 
 
 
X 
X 
 
X 
Photography 
**X 
X 
**X 
X 
**X 
**X 
X 
Ultrasound 
 
X 
 
X 
 
 
X 
CoolMini Treatment 
 
X 
X 
 
 
 
 
KYBELLA® 
Treatment 
 
 
 
X 
**X 
 
 
 
X 
X 
X 
X 
X 
X 
AE Assessment 
 
X 
X 
X 
X 
X 
X 
Subject Self Rated 
Scale 
X 
 
 
X 
 
 
X 
* Informed consent to be signed by subject prior to the collection of any data or completion of any study 
procedures.  
** Optional  
† Follow-up after each treatment 
 
 
2.13. 
Assessments 
Study-related assessments are described below. 
2.13.1. 
Safety Assessments 
The primary safety endpoint is the incidence, seriousness, severity and 
duration of device, drug and/or procedure-related adverse events at the final 
follow-up visit. Safety will be monitored by documentation of adverse events 
and clinical assessment of the treatment site.  


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2.13.2. 
Clinician Evaluation using CR-SMFRS 
The primary measure will be clinician live assessment of the patient’s 
severity of submental fat as determined by the CR-SMFRS (Table 3).   
The CR-SMFRS score will be based on the investigator’s clinical evaluation 
of the subject, including palpation of the chin and neck area; anterior, 
oblique, and profile views of the chin and neck; and observation of pronation, 
supination, and lateral movement of the head. The score will be determined 
using the rating scale definitions and the representative photographs 
associated with each score. The final score will be determined while the 
subject’s head is in the Frankfort plane posture as described in the CR-
SMFRS. The score will be recorded as a whole number. 
 
Table 3.    Clinician Reported-Submental Fat Rating Scale (CR-SMFRS) 
 
Score 
SMF Description 
0 
Absent Submental Convexity: No localized submental fat 
evident. 
1 
Mild Submental Convexity: Minimal, localized 
submental fat. 
2 
Moderate Submental Convexity: Prominent, localized 
submental fat. 
3 
Severe Submental Convexity: Marked, localized 
submental fat. 
4 
Extreme Submental Convexity. 
 
2.13.3. 
Photography   
Photography will be performed by a qualified representative of the sponsor.    
 
A series of photos of the treatment areas will be obtained at the pre-
treatment, prior to first KYBELLA® injection (Treatment visit 3) and final 
follow-up visits, using custom standardized setup, lighting, and camera 
settings to ensure consistency. All photographs will be captured at fixed 
angles and posture (Frankfort plane). Using a series of pre-determined 
markings on the floor, the photographer will position the camera at the pre-
determined reference points to ensure that the reproduction ratio and focal 


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distance are maintained throughout the image series during the study.  During 
follow-up visits, the photographer will re-align subjects by referencing 
baseline images.  
2.13.4. 
Ultrasound Measurements  
Ultrasounds will be performed by a qualified representative of the sponsor.    
 
After treatment sites have been identified, the ultrasound measurement 
locations will be marked.  Up to 3 measurement locations will be marked on 
the intended treatment area.  A template may be created prior to treatment to 
mark the locations for ultrasound measurements.  This template 
(transparency) will be created using external landmarks (e.g., skin 
imperfections) as reference points, identifying the peak of the bulge and the 
locations for ultrasound measurements.  At follow-up visits, the template will 
be used to mark the locations for ultrasound measurements. A SonoSite 
TITAN® ultrasound system (or equivalent approved by Sponsor) will be used 
in this study.  A high frequency linear transducer array (L38/10-5: 38-mm 
broadband, 10-5 MHz, optimized for breast, small parts, interventional, 
musculoskeletal and vascular imaging) provides sufficient spatial resolution 
to visualize anatomical features for image plane alignment for fat layer 
measurement.  Stored images will be transferred to an off-line PC based 
image analysis tool for fat layer measurements.  These files will be stored by 
the Sponsor and indexed by subject identifier.  Standardized techniques for 
obtaining images will be used to ensure consistency throughout the study.  
 
The individual(s) analyzing the images will be presented with two series of 
images for each measurement site, the pre-treatment and the final post-
treatment series, and asked to measure the depth of fat layer in each image.  
The order in which the images are presented will be randomized by subject.    
2.13.5. 
Subject Self-Rating Scale (SSRS)   
Subject’s assessment of overall satisfaction with their face and chin using the 
SSRS will be obtained at Screening (baseline score), at Treatment Visit 3 
(prior to first KYBELLA® treatment) and at the final 12-week follow-up 
visit.   
SSRS is a subject self-rating scale, scored on a 7-point scale with 
0=extremely dissatisfied, 1=dissatisfied, 2=slightly dissatisfied, 3=neither 
satisfied not dissatisfied, 4=slightly satisfied, 5=satisfied, and 6=extremely 
satisfied.   


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Title: Fat Reduction in the Submental Area – A Sequential Treatment Approach 
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2.14. 
Endpoints 
The objective of this study is to evaluate the safety and efficacy of subcutaneous fat layer 
reduction in the submental area on subjects with extreme submental fullness defined by 
the CR-SMFRS as Grade 4 using CoolSculpting and KYBELLA® in sequence. 
2.14.1. 
Primary Endpoints 
The primary endpoints of the study will be defined as follows: 
• Safety endpoint: incidence of device, drug or procedure-related adverse 
events.   
 
• Efficacy endpoint:  
1. 
The reduction, from baseline (CR-SMFRS =4) to final follow-up, 
of submental fat (SMF) as assessed by the proportion of subjects who 
have at least a 1-grade improvement on the Clinician Reported Submental 
Fat Rating Scale (CR-SMFRS), and 
 
2. 
The reduction, from baseline (CR-SMFRS=4) to final follow-up, 
of SMF as assessed by the proportion of subjects who have at least a 2-
grade improvement on the CR-SMFRS. 
 
2.14.2. 
Secondary Endpoints 
Secondary endpoints in the study are as follows: 
1. Reduction in fat layer thickness, as measured by ultrasound at Week 
12 post-final treatment. 
2. Subject satisfaction as assessed by Subject Self-Rating Scale scores.  
 
2.15. 
Statistical Analysis Plan 
2.15.1. 
Statistical Methods: Overall Plan 
Data will be summarized based on the nature of the data.  Dichotomous (e.g., 
gender, independent photographic review) and ordinal (e.g., Fitzpatrick Skin 
type) data will be tabulated by category.  The mean, standard deviation, 
maximum, and minimum will be tabulated for continuous data (e.g., age, fat 
thickness).  The significance level will be two-sided 0.05 for all statistical 
tests. 
 


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2.15.2. 
Analysis Population 
Analysis Populations are defined as following: 
Per-protocol Population (PP): 
The Per-protocol Population will consist of all the treated subjects followed 
through to the final post-treatment visit and with weight change of no more 
than five percent at the time the final post-treatment visit images are taken.  
Since a weight change of more than 5 percent will affect the images, the 
primary Efficacy analysis will be performed based on this study population. 
Subjects who do not complete the treatment or had an interruption in the 
treatment will not be included in the primary and secondary Efficacy 
analyses. 
 
As-Treated Population (AT): 
This population consists of all treated subjects regardless of whether they 
become pregnant, undergo weight change during the study, or had interrupted 
treatment.   
 
Safety Population (SA): 
This population will consist of all the treated subjects with safety evaluation 
after the treatment.  This population should be identical to the AT population.  
The safety data analyses will be performed based on the Safety Population. 
2.15.3. 
Endpoint Analysis 
2.15.3.1. Primary Safety Endpoint: 
The primary safety endpoint is incidence of all device, drug – and/or 
procedure-related adverse events.  All adverse events reported during and 
following the treatment will be included in the safety analysis.  The 
frequency and proportion of subjects reporting each type of adverse event 
will be tabulated by relationship with the treatment and seriousness as well as 
severity of the event. 
 


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Title: Fat Reduction in the Submental Area – A Sequential Treatment Approach 
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2.15.3.2. Primary Efficacy Endpoint: Reduction in CR-Submental Fat Rating 
Scale 
The primary efficacy endpoint is the change in subcutaneous fat layer in the 
submental area as measured between the baseline and final post-treatment 
visit CR-Submental Fat Rating Scale scores.  Since weight change may affect 
the fat layer thickness, the analysis will be based on the evaluation of the PP 
population, i.e. treated subjects followed through to the final post-treatment 
visit who did not become pregnant, and with weight change of no more than 
5 percent at the final post-treatment visit.   
 
2.15.3.3. Secondary Endpoint: Ultrasound 
A secondary efficacy endpoint is the change in subcutaneous fat layer as 
measured between the pre- and final post-treatment visit images.  Since 
weight change may affect the fat layer thickness, the analysis will be based 
on the evaluation of the PP population, i.e. treated subjects followed through 
to the final post-treatment visit who did not become pregnant, and with 
weight change of no more than 5 percent at the final post-treatment visit.     
2.15.3.4. Secondary Endpoint: Subject Self-Rating Scale  
 
 
 
2.15.3.5. Sample Size Requirement 
Up to twenty (20) subjects is thought to be appropriate to provide feasibility 
information regarding safety and efficacy of submental treatment using 
CoolMini vacuum applicator and KYBELLA® sequentially.     
2.16. 
Missing Data Handling 
In general, no imputation for missing data will be made. Data will be analyzed “as-is” 
where subjects with missing data not being included in the analysis. 
2.17. 
Protocol Adherence 
The study investigators are responsible for performing the study in compliance with the 
protocol.   Non-adherence to the protocol is to be classified as a protocol violation or 
protocol deviation, as defined below. 
 
Protocol Violation 


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Non-adherence to the protocol that may result in significant additional risk to the subject 
(e.g., enrollment of a subject who does not meet the study criteria).  Or, non-adherence to 
Good Clinical Practices (GCP) that may impact patient safety (e.g., failure to obtain 
proper consent prior to performing study procedures).  Violations should be reported to 
the study Sponsor within 5 working days and reported to the IRB per IRB guidelines. 
 
Protocol Deviation 
 
Non-adherence to study procedures which does not result in additional risk to the subject 
(e.g., subject missed visit).  Protocol deviations are not required to be reported to the 
IRB; however, they must be recorded on the study case report forms and may be reported 
and reviewed in conjunction with the progress report as part of the annual review process. 
 
2.18. 
Adverse Events 
Adverse events (AE) will be assessed continuously throughout the study. An AE is 
defined in accordance with ISO 14155 as any untoward medical occurrence, unintended 
disease or injury, or untoward clinical signs (including abnormal laboratory findings)  in 
study participants, users, or other persons temporally associated with the use of study 
treatment, whether or not considered related to the study treatment. 
 
Disease signs and symptoms that existed prior to the study treatment are not considered 
AEs unless the condition recurs after the patient has recovered from the pre-existing 
condition or the condition worsens in intensity or frequency during the study.  
 
AEs will be monitored throughout the study beginning with signing of informed consent. 
At each post-baseline visit, the investigator will begin querying for AEs by asking each 
patient a general, non-directed question such as “Have you had any changes to your 
condition since your last visit?” Previous AEs and changes in therapy/concomitant 
medications are to be updated. Directed questioning and examination will then be done as 
appropriate. All reportable AEs and clinically significant abnormal laboratory findings 
will be documented on the appropriate CRF. 
 
Adverse events will be reported by the participant (or, when appropriate, by a caregiver, 
surrogate, or the participant's legally authorized representative). The investigator and any 
designees are responsible for detecting, documenting, and recording events that meet the 
definition of an AE or SAE and remain responsible for following up AEs that are serious, 
considered related to the study treatment or study procedures, or that caused the 
participant to discontinue the study 
 


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with CoolMini and KYBELLA® 
 
 
ZELTIQ P/N: 
Protocol Number: ZA17-005 
 
This document and the contents hereof are considered proprietary and confidential information of ZELTIQ Aesthetics, 
Inc.  Disclosure to unauthorized individuals or dissemination, publication or copying is prohibited without prior written consent 
of ZELTIQ. 
Adverse Device Effect (ADE) 
 
Any sign, symptom, or disease in a study subject that occurs during the course of a 
clinical trial that is determined by the Investigator to have a causal relationship or 
possible causal relationship with the device under investigation. This definition includes 
any AE s resulting from insufficient or inadequate instructions for use, deployment, 
implantation, installation, or operation, or any malfunction of the investigational medical 
device as well as any event resulting from use error (per ISO 62366) or from intentional 
misuse of the investigational medical device.  
 
Serious Adverse Device Effect (SADE) 
 
A serious adverse device effect (SADE) is defined in accordance with ISO 14155 as “an 
adverse device effect that has resulted in any of the consequences characteristic of a 
serious adverse event.” 
 
Unanticipated Serious Adverse Device Effect (USADE) 
 
An unanticipated serious adverse device effect (USADE) is defined in accordance with 
ISO 14155 as “any serious adverse device effect which by its nature, incidence, severity, 
or outcome has not been identified in the current version of the risk analysis report.” The 
investigator is to consult the IDFU for anticipated risks or anticipated AEs. 
 
Device Deficiency  
 
A device deficiency is defined in accordance with ISO 14155 as “inadequacy of a 
medical device with respect to its identity, quality, durability, reliability, safety, or 
performance.” Device deficiencies include malfunctions, use errors, and inadequate 
labeling. 
 
If a device deficiency occurs, the investigator will notify the Sponsor using the fax 
number or email on the front page of the protocol. Device deficiencies shall be 
documented throughout the study and appropriately managed by the Sponsor. The 
Sponsor shall review all device deficiencies and determine and document in writing 
whether they could have led to an SADE. These shall be reported to the regulatory 
authorities and IRBs/ECs as required by national regulations. 
 
Serious Adverse Event (SAE) 
 
An SAE is defined in accordance with ISO 14155 as an AE that: 
 
1. Led to death 


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ZELTIQ P/N: 
Protocol Number: ZA17-005 
 
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Inc.  Disclosure to unauthorized individuals or dissemination, publication or copying is prohibited without prior written consent 
of ZELTIQ. 
2. Led to serious deterioration in the health of the patient, that either resulted in: 
a. a life-threatening illness or injury, or 
b. a permanent impairment of a body structure or a body function, or 
c. inpatient or prolonged hospitalization, or 
d. medical or surgical intervention to prevent life-threatening illness or 
injury or permanent impairment to a body structure or a body function, 
or 
e. led to fetal distress, fetal death or a congenital abnormality or birth 
defect 
NOTE: Planned hospitalization for a pre-existing condition, or a procedure required by 
the protocol, without serious deterioration in health, is not considered an SAE. 
 
Time Period and Frequency for Collecting AE and SAE Information 
 
All AEs and SAEs from the signing of the ICF until the last follow-up visit will be 
collected at the timepoints specified in the schedule of activities, and as observed or 
reported spontaneously by study participants.  
 
Medical occurrences that begin after signing of informed consent and before 
administration of study treatment will be recorded as an AE on the appropriate CRF. 
 
All SAEs will be recorded and reported to the sponsor or designee within 24 hours of 
learning about the report. All non-serious AEs related to the devices used in the study, as 
well as Device Complaints, will be reported to the sponsor within 7 working days. The 
investigator will submit any updates on these events to the sponsor within 24 hours of it 
being available. 
 
Investigators are not obligated to actively seek AE or SAE in former study participants. 
However, if the investigator learns of any SAE, including a death, at any time after a 
participant has completed the final visit of the study, and he/she considers the event to be 
reasonably related to the study treatment or study participation, the investigator must 
promptly report the event to the sponsor. 
 
Method of Detecting AEs and SAEs 
 
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended 
and non-leading verbal questioning of the participant is the preferred method to inquire 
about possible AEs. 
 
Follow-up of AEs and SAEs 
 


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Title: Fat Reduction in the Submental Area – A Sequential Treatment Approach 
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ZELTIQ P/N: 
Protocol Number: ZA17-005 
 
This document and the contents hereof are considered proprietary and confidential information of ZELTIQ Aesthetics, 
Inc.  Disclosure to unauthorized individuals or dissemination, publication or copying is prohibited without prior written consent 
of ZELTIQ. 
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. All SAEs will be followed until resolution, 
stabilization, the event is otherwise explained, or the participant is lost to follow-up. 
 
The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by the sponsor to 
elucidate the nature and/or causality of the AE or SAE as fully as possible. This may 
include additional laboratory tests or investigations, histopathological examinations, or 
consultation with other health care professionals. 
 
New or updated information will be recorded in the originally completed CRF. 
 
The investigator will submit any updated SAE data to the sponsor within 24 hours of 
receipt of the information. 
 
Reportable Incidents 
 
Serious adverse events (SAEs) and unanticipated adverse device effects (UADEs) must 
be reported within 24 hours of knowledge of the event to the Sponsor. 
All adverse events observed by the investigator or reported by the subject will be 
recorded on the appropriate CRF, irrespective of relationship to CoolSculpting and 
KYBELLA®, as well as the KYBELLA® skin grid.  Medically significant adverse events 
will be followed until resolved or considered stable. For each event, the investigator will 
record a description, dates of onset and resolution, severity, and relationship to 
CoolSculpting, KYBELLA® and KYBELLA® skin grid. The investigator may be 
required to provide follow-up information. 
Any adverse event that results in withdrawal from the study must be reported to the 
Sponsor after the decision to withdraw the subject is made. 
Any death occurring during the study must be reported to the Sponsor within 24 hours of 
the discovery of the event. This includes any death that occurs within 30 days after the 
subject's final visit, irrespective of when the final visit occurs. 
Assessment of Severity 
Severity of adverse events will be determined using the following scale: 
• 
Mild: Event that is easily tolerated and may require only minimal treatment 
or therapeutic intervention. The event does not generally interfere with 
usual activities of daily living. 


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Title: Fat Reduction in the Submental Area – A Sequential Treatment Approach 
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Protocol Number: ZA17-005 
 
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Inc.  Disclosure to unauthorized individuals or dissemination, publication or copying is prohibited without prior written consent 
of ZELTIQ. 
• 
Moderate: Events that interfere with usual activities of daily living, causing 
discomfort but poses no significant or permanent risk of harm to the 
research participant. It is usually alleviated with additional specific 
therapeutic intervention.  
• 
Severe: Event that is incapacitating, with inability to work and do the 
usual activities of daily living, or significantly affects clinical status. This 
may require intensive therapeutic intervention. 
Assessment of Causality 
• The investigator is obligated to assess the relationship between study treatment and 
each occurrence of each AE/SAE. 
• A reasonable possibility of a relationship conveys that there are facts, evidence, 
and/or arguments to suggest a causal relationship, rather than a relationship cannot 
be ruled out. 
• The investigator will use clinical judgment to determine the relationship. 
• Alternative causes, such as underlying disease(s), concomitant therapy, and other 
risk factors, as well as the temporal relationship of the event to study treatment 
administration will be considered and investigated. 
• The investigator will also consult the investigator’s brochure and/or product 
information, for marketed products, in his/her assessment. 
• For each AE/SAE, the investigator must document in the medical notes that he/she 
has reviewed the AE/SAE and has provided an assessment of causality. 
• For each AE/SAE, there are 5 levels of causality, as follows: 
• 
Not related 
• 
Unlikely 
• 
Possible 
• 
Probable 
• 
Causal relationship 
 


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ZELTIQ P/N: 
Protocol Number: ZA17-005 
 
This document and the contents hereof are considered proprietary and confidential information of ZELTIQ Aesthetics, 
Inc.  Disclosure to unauthorized individuals or dissemination, publication or copying is prohibited without prior written consent 
of ZELTIQ. 
• There may be situations in which an SAE has occurred and the investigator has 
minimal information to include in the initial report to the sponsor. However, it is 
very important that the investigator always make an assessment of causality for 
every event before the initial transmission of the SAE data to the sponsor. 
• The investigator may change his/her opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality 
assessment. 
• The causality assessment is one of the criteria used when determining regulatory 
reporting requirements. 
The investigator will determine the relationship of each adverse event to CoolSculpting 
and/or KYBELLA® using the question: "Is there a reasonable possibility that the event 
may have been caused by treatment with CoolSculpting and/or KYBELLA®? Answer 
'yes' or 'no' for each adverse event." 
The guideline below should be used to consider relatedness: 
For a “no causal relationship” assessment, the adverse event:  
• 
May be judged to be due to extraneous causes such as disease or 
environment or toxic factors 
• 
May be judged to be due to the subject's clinical state or other therapy 
being administered   
• 
Is not biologically plausible 
• 
Does not reappear or worsen when CoolSculpting and/or KYBELLA® is 
re-administered 
• 
Does not follow a temporal sequence from treatment with CoolSculpting 
or administration of KYBELLA® 
For a causal relationship (including unlikely, probable and possible assessments) 
there is a reasonable possibility that the event may have been caused by 
CoolSculpting,  KYBELLA® and/or the KYBELLA® Grid.   The adverse event: 
• 
Follows a temporal sequence from treatment with CoolSculpting and/or 
administration of KYBELLA® 
• 
Is a known response to CoolSculpting and/or KYBELLA® based on 
clinical or nonclinical data 


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Protocol Number: ZA17-005 
 
This document and the contents hereof are considered proprietary and confidential information of ZELTIQ Aesthetics, 
Inc.  Disclosure to unauthorized individuals or dissemination, publication or copying is prohibited without prior written consent 
of ZELTIQ. 
• 
Could not be explained by the known characteristics of the subject's 
clinical state, environmental or toxic factors, or other therapy administered 
• 
Disappears or decreases upon cessation of CoolSculpting and/or 
KYBELLA® tx or reduction in total dose of KYBELLA® 
• 
Reappears or worsens when CoolSculpting and/or KYBELLA® is re-   
administered 
Serious Adverse Event Reporting Procedures 
All serious adverse events must be reported to the Sponsor within 1 working day of 
discovery or notification of the event and according to IEC/IRB requirements and the 
institution at which the study is conducted, if applicable. Serious adverse event information 
and any follow-up information will be recorded on a Serious Adverse Event Form and 
transmitted to the Sponsor using the contact information provided by the Sponsor. Note 
that for each drug/device used in this study, a separate SAE form and contact information 
will be used. The Sponsor will be responsible for evaluating and reporting any serious 
adverse events and suspected unexpected serious adverse reactions in accordance with all 
applicable laws and regulations. 
Safety Monitoring Considerations 
If an adverse event occurs that in the judgment of the investigator represents a potential 
risk for new subjects, the investigator will contact the Sponsor within 1 working day after 
becoming aware of the event. 
A full reporting of the event shall be provided within 10 working days of the event.  The 
Sponsor is then responsible for notifying the IRB, as required. 
Pregnancy 
o Details of all pregnancies in female participants will be collected after the start of study 
treatment through the duration of the pregnancy. 
o If a pregnancy is reported, the investigator should inform the sponsor within 24 hours 
of learning of the pregnancy.  
o If a female of childbearing potential becomes pregnant during the study, the 
investigator should notify the participant’s physician that the participant may have been 
treated with KYBELLA® and/or CoolSculpting and exit the participant from the study. 
o Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAEs. 


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ZELTIQ P/N: 
Protocol Number: ZA17-005 
 
This document and the contents hereof are considered proprietary and confidential information of ZELTIQ Aesthetics, 
Inc.  Disclosure to unauthorized individuals or dissemination, publication or copying is prohibited without prior written consent 
of ZELTIQ. 
o A pregnancy form will need to be filled out by the site and submitted to the sponsor.  
3. Study Management and Quality Control  
3.1. 
Study Data Collection   
Standardized Case Report Forms (CRFs) will be provided to all participating sites.  Data 
will be reviewed by the study monitor and Sponsor data management personnel to 
identify inconsistent or missing data and to ensure compliance with the study protocol. 
3.2. 
Confidentiality 
All information and data concerning study subjects will be considered confidential, and 
handled in compliance with all applicable regulations including the requirements of the 
Health Insurance Portability and Accountability Act (HIPAA) of 1996. 
Only authorized site staff, the study Sponsor or the Sponsor’s designee, IRB and relevant 
Regulatory authorities will have access to these confidential files. A unique identification 
code will be assigned to each subject participating in this trial. All data used in the 
analysis, reporting and publication of this clinical trial will be maintained without 
identifiable reference to the subject. Any data that may be published in abstracts, 
scientific journals, or presented at medical meetings will reference a unique subject code 
and will not reveal the subject’s identity. 
3.3. 
Investigator Responsibilities 
3.3.1. 
General Responsibilities   
Investigators are responsible for ensuring the investigation is conducted 
according to all signed agreements, the Investigational Plan, and applicable 
FDA regulations.  The investigator must protect the rights, safety, privacy 
and welfare of the subjects under the Investigator’s care. Investigators will 
assume overall responsibility and accountability for study site staff and for 
the clinical data obtained during the study.  The investigator assumes all 
responsibilities per 21 CFR 812, 21 CFR 312, and other applicable 
regulations, including but not limited to: 
IRB Approval 
The investigator may not begin the study until the governing institutional 
review board (IRB) provides written approval of the study protocol and 
consent form.  The investigator is also responsible for fulfilling any 
conditions of approval imposed by the IRB. 
Informed Consent 


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Protocol Number: ZA17-005 
 
This document and the contents hereof are considered proprietary and confidential information of ZELTIQ Aesthetics, 
Inc.  Disclosure to unauthorized individuals or dissemination, publication or copying is prohibited without prior written consent 
of ZELTIQ. 
The investigator must ensure that informed consent is obtained from each 
prospective study subject in accordance with 21 CFR Part 50 and that the 
study is not commenced until IRB approval has been obtained.   
Device and Drug Accountability 
Device and drug accountability is not applicable for this non-significant risk 
study. 
KYBELLA® is to be stored at room temperature in a locked storage area and, 
not to be exposed to extreme temperature (greater than 30°C or less than 15°C). 
Financial Disclosure 
Investigators shall provide financial disclosure according to federal 
regulations (21 CFR 54).  
Study Coordinator 
To assure proper execution of the study protocol, each investigator must 
identify a study coordinator for the site who will work with and under the 
authority of the investigator to assure that study requirements are fulfilled as 
appropriate. 
3.3.2. 
Investigator Records 
The investigator and study staff must maintain accurate, complete, and 
current records relating to the conduct of the investigation.  Records must be 
retained for a period of two years following (1) the date the investigation was 
completed or terminated, or (2) the records are no longer required to support 
a regulatory submission or completion of a product development protocol, 
whichever is longer.  Participating investigators shall maintain the following:  
• All correspondence with the Sponsor, another investigator, the IRB, 
and a monitor 
• Records of all persons authorized to conduct the study (e.g. 
Delegation of Duties/Signature Authorization, CV) 
• Informed Consent documentation for all enrolled subjects 
• Records of each subject's case history, including study-required Case 
Report Forms and source documentation (e.g. physician notes, lab 
reports, study worksheets, clinic charts) 
• All relevant observations of adverse device effects 
• Records of any protocol deviations 


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ZELTIQ P/N: 
Protocol Number: ZA17-005 
 
This document and the contents hereof are considered proprietary and confidential information of ZELTIQ Aesthetics, 
Inc.  Disclosure to unauthorized individuals or dissemination, publication or copying is prohibited without prior written consent 
of ZELTIQ. 
• The condition of each subject upon entering and during the course of 
the investigation and any relevant medical history and results of any 
diagnostic tests 
• Investigational plan with all amendments 
• Current IRB approved informed consent and all previously approved 
versions 
• Signed Investigator agreement 
• Investigators will be responsible for the accurate and timely 
completion of CRFs during the trial.   
These records must be available and suitable for inspection at any time by 
Sponsor representatives (monitor), or the reviewing IRB. The Investigator 
will supply access to study-related medical records, original laboratory data, 
and other records and data as they relate to the trial.  The investigator will 
ensure that both he/she and his/her study staff have adequate time and 
resources to devote to the study, including study enrollment, subject 
evaluations, study documentation and site monitoring. 
3.3.3. 
Investigator Reports 
The investigator is responsible for preparation and submission of the 
following reports: 
• Report of any unanticipated adverse device effects or life-threatening 
suspected adverse reactions shall be submitted to the Sponsor within 
1 working day after the Investigator first learns of the effect. 
• Withdrawal of IRB approval of the investigator’s part in the 
investigation shall be reported to the Sponsor within 5 working days. 
• Progress reports on the investigation to the sponsor, the monitor, and 
the reviewing IRB annually. Alternatively, the Sponsor may prepare 
the report.  
• Deviations from the investigational plan shall be reported to the 
Sponsor and the IRB. 
• Failure to obtain informed consent prior to use of a device in a subject 
shall be reported to the Sponsor and IRB within 5 working days after 
the use occurs. 
A final report shall be submitted to the Sponsor and IRB within 3 months 
after termination or completion of the investigation, or the investigator’s part 
of the investigation. 


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ZELTIQ P/N: 
Protocol Number: ZA17-005 
 
This document and the contents hereof are considered proprietary and confidential information of ZELTIQ Aesthetics, 
Inc.  Disclosure to unauthorized individuals or dissemination, publication or copying is prohibited without prior written consent 
of ZELTIQ. 
3.4. 
Sponsor Responsibilities  
3.4.1. 
General Responsibilities: 
As the Sponsor, ZELTIQ Aesthetics an Allergan affiliate assumes overall 
responsibility for the conduct of the study. ZELTIQ Aesthetics assumes all 
responsibilities per 21 CFR 812 and other applicable regulations, and shall: 
IRB approval: Ensure IRB approval for the investigation before shipping 
the device to any Investigator.  
Investigators:  Select Investigators qualified by training and experience, and 
providing them with the information they need to conduct the investigation 
properly. Obtain a signed Investigator Agreement and Form FDA-1572 from 
each participating Investigator. Study sites will be evaluated to ensure that 
they have an adequate patient base and can provide sufficient staff and 
documentation support to conduct the study properly. 
Monitoring:  Select monitors qualified by training and experience to 
monitoring the study and ensure proper monitoring of the investigation.  
Data Management and analysis:  Ensure data collection, verification, 
analysis, records storage, etc. Sponsor will assist with presentation(s) and/or 
publication(s). 
3.4.2. 
Training  
Study Training: To ensure uniform data collection and protocol compliance, 
Sponsor personnel will provide an educational session to study site personnel 
as needed, which will cover the Investigational Plan, techniques for the 
identification of eligible subjects, study assessments, data collection and 
form completion, and the device directions for use as well as the drug 
labeling (including full prescribing information).  The Investigator and study 
staff will be trained on the study device, drug and protocol, applicable 
regulations and requirements, and expectations of the study, enrollment 
expectations, subject selection, informed consent, required clinical data and 
record keeping, etc.   
Study Material Use: Representatives of the Sponsor will train site staff in 
use of the study device and drug prior to study initiation.  Sponsor 
representatives may be present at study procedures. 


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Title: Fat Reduction in the Submental Area – A Sequential Treatment Approach 
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ZELTIQ P/N: 
Protocol Number: ZA17-005 
 
This document and the contents hereof are considered proprietary and confidential information of ZELTIQ Aesthetics, 
Inc.  Disclosure to unauthorized individuals or dissemination, publication or copying is prohibited without prior written consent 
of ZELTIQ. 
3.4.3. 
Site Monitoring  
The Sponsor will ensure that qualified clinical monitors are available to 
monitor and oversee the conduct of the trial and that monitoring is performed 
in accordance with the Sponsor’s approved procedures or third-party 
procedures approved by the Sponsor.  
The clinical monitors will evaluate compliance with the investigational plan, 
FDA regulations, any specific recommendations made by the site’s IRB and 
the signed Investigator Agreement.   
Monitoring Visits 
On-site monitoring visits will assess the progress of the clinical study and 
identify any concerns that result from the study drug or device performance 
or review of the Investigator’s study records, study management documents, 
and informed consent documents.   
Monitoring will ensure continued protocol compliance and accurate data 
reporting. Monitoring visits will occur at minimum once before study close-
out. 
During monitoring visits, the monitor will compare subject records and other 
supporting documents with reports at the site to determine that; 
• The facilities used by the investigation continue to be acceptable 
for the purposes of the clinical study 
• Informed consent was properly obtained and documented for all 
enrolled study participants 
• The Investigational Plan is being followed, and only eligible 
subjects are being enrolled into the study 
• Deviations to the Investigational Plan have been reported to 
ZELTIQ and the IRB, as appropriate 
• Adverse events are promptly being reported 
• Information recorded in the case report forms and study reports are 
accurate, complete, legible and consistent with source 
documentation.  
• Subjects failing to complete the clinical study and the reason for 
failure are recorded. 
• Missed follow-up visits are noted in the study documentation 
Clinical monitors will provide feedback to the site regarding protocol or 
study compliance. 


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Title: Fat Reduction in the Submental Area – A Sequential Treatment Approach 
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This document and the contents hereof are considered proprietary and confidential information of ZELTIQ Aesthetics, 
Inc.  Disclosure to unauthorized individuals or dissemination, publication or copying is prohibited without prior written consent 
of ZELTIQ. 
Study Site Closeout   
At the close of the study at an investigational site, the monitor will ensure 
that all case report forms have been monitored and retrieved and that the 
Investigator’s files are accurate and complete. The monitor will ensure that 
all investigational devices, drugs and study supplies are accounted for, and 
provide for appropriate disposition of any remaining supplies. The monitor 
will review record retention requirements with the Investigator and any 
remaining Investigator obligations are reviewed and ensure that all applicable 
requirements are met for the study.  The monitor will prepare a report of the 
site closeout visit.  
3.4.4. 
Final Report  
A final report will be prepared at the conclusion of the trial. Copies of the 
final report will be provided to each Investigator and to the respective IRB. 
3.4.5. 
Trial Registration  
Prior to study initiation, the trial will be registered, if applicable, on a 
publicly accessible study database such as clinicaltrials.gov. 
4. Data Ownership 
ZELTIQ Aesthetics an Allergan affiliate, the study Sponsor, retains ownership of all data 
generated in this study, and controls the use of the data for purposes of regulatory submissions to 
the US and/or other governments. Investigator(s) and institution(s) (which shall include their 
employees, agents, and representatives) may not issue or disseminate any press release or 
statement, nor initiate any communication of information regarding this study (written or oral) to 
the communications media or third parties without the prior written consent of the Sponsor.  
5. Publication Policy 
Participating Investigators and/or Institutions may publish information or data collected or 
produced as a result of participation in appropriate scientific conference or journals or other 
professional publications subject to written permission from the Sponsor, provided that drafts of 
the material are provided to the Sponsor for purposes of review and comment at least sixty (60) 
days prior to the first submission for publication or public release.  Investigators may not publish 
information regarding site-specific data until a multicenter study report has been published.  
6. Risk/Benefit Analysis 
The Sponsor has undertaken a comprehensive risk-benefit analysis. 


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This document and the contents hereof are considered proprietary and confidential information of ZELTIQ Aesthetics, 
Inc.  Disclosure to unauthorized individuals or dissemination, publication or copying is prohibited without prior written consent 
of ZELTIQ. 
6.1. 
Benefits 
Fat reduction in the treatment area is anticipated to provide an aesthetic benefit and the 
use of this minimally-invasive drug and non-invasive device will eliminate the need for 
an invasive procedure that requires anesthesia or recovery time.  Furthermore, the results 
of this study will help in the development of optimal treatment regimens for specific 
submental fullness severities.  Considering the number of surgical procedures performed 
for the removal of fat each year (over 1.8 million procedures worldwide, according to the 
2016 International Society of Aesthetic Plastic Surgeons Biennial Global Survey), the use 
of such a minimally-invasive and non-invasive procedure has the potential to 
significantly reduce the incidence of complications and post-surgical limitations 
associated with those procedures. 
6.2. 
Risks 
Although this study presents minimal risks to the subject, there is the potential for some 
risk when any medical procedure is performed.  
 
Anticipated Device Effects 
 
 
These are known effects of the CoolSculpting Procedure, previously recorded in prior 
studies as transient and/or temporary effects related to the cold application and/or vacuum 
pressure inherent in the treatment. Anticipated effects of the device which will not be 
considered adverse events include:  
 
• inflammation of the subcutaneous fat layer, which is a desired effect of the procedure; 
• sensations of coldness, stinging, burning, pinching, or pressure associated with 
placement of the applicator and the initiation of the cold treatment; 
• known skin effects (e.g., blanching; erythema, bruising, purpura, petechiae, swelling, 
discomfort, tenderness, or soreness at the treatment site, all mild to moderate in 
nature) which are temporary effects that resolve spontaneously shortly after the 
procedure; 
• localized sensory changes (e.g., numbness, tingling) at the treatment area resolving 
within 12 weeks of the procedure. 
 
Adverse Effects for CoolSculpting 
 
The following summarizes the potential adverse effects from CoolSculpting in this study: 
 


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Title: Fat Reduction in the Submental Area – A Sequential Treatment Approach 
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Inc.  Disclosure to unauthorized individuals or dissemination, publication or copying is prohibited without prior written consent 
of ZELTIQ. 
Potential Adverse Effect 
Description 
Severe Bruising 
The appearance of bruising (purple discoloration); purpura 
(purple colored spots or patches); or petechiae (pin point red 
dots) that is rated as severe by the investigator;  
Prolonged Bruising 
Bruising lasting longer than 1 month 
Severe Erythema 
The appearance of erythema (redness) that is rated as severe 
by the investigator  
Prolonged erythema 
Erythema lasting longer than 2 weeks. 
Severe Swelling 
The appearance of swelling (edema) that is rated as severe by 
the investigator  
Prolonged swelling 
Swelling lasting longer than 1 month. 
First Degree Burn 
 
A first-degree burn is superficial and causes local 
inflammation of the skin. The inflammation is characterized 
by pain, redness, and mild swelling. The skin may be very 
tender to touch. 
Second Degree Burn 
Second degree burns are deeper and in addition to the pain, 
redness and inflammation, there is also blistering of the skin.  
Third Degree Burn 
Third degree burns are deeper still, involving all layers of the 
skin.  Because the nerves and blood vessels are damaged, 
third degree burns appear white, leathery and tend to be 
relatively painless. 
Cold-induced Panniculitis 
Severe inflammation which requires medical or surgical 
intervention. 
Skin Pigment Changes 
The appearance of hyperpigmentation or hypopigmentation in 
the treatment area. 
Infection 
Infection at the treatment site, diagnosed by a Physician and 
requiring medical intervention. 
Discomfort During 
Procedure 
Discomfort reported during the procedure that is intolerable to 
the subject and results in an interruption or discontinuation of 
the procedure 
Discomfort Post Procedure 
Significant discomfort, pain, cramping, tenderness, soreness, 
muscle spasm following the procedure which results in 
medical intervention (physician visit and/or prescription pain 
reliever) 
Prolonged Sensory 
Alteration Post Procedure 
Sensory changes (numbness, tingling, burning sensation) that 
are prolonged (i.e., lasting longer than 12 weeks). 
Sensory Alteration 
Requiring Medical 
Intervention 
Sensory changes (pain, burning, stinging, hypersensitivity) 
with a severity warranting medical intervention. 


ZELTIQ Aesthetics – Confidential and Proprietary  
 
 
Part Number: 
 Revision: 01 
Page 44 of 46 
Title: Fat Reduction in the Submental Area – A Sequential Treatment Approach 
with CoolMini and KYBELLA® 
 
 
ZELTIQ P/N: 
Protocol Number: ZA17-005 
 
This document and the contents hereof are considered proprietary and confidential information of ZELTIQ Aesthetics, 
Inc.  Disclosure to unauthorized individuals or dissemination, publication or copying is prohibited without prior written consent 
of ZELTIQ. 
Potential Adverse Effect 
Description 
Vasovagal Symptoms 
The occurrence of symptoms of anxiety, lightheadedness, 
dizziness, nausea, sweating, near syncope, or syncope 
(fainting). 
Motor Nerve Injury 
Injury to the lower face motor nerves such as marginal 
mandibular nerve (lower lip weakness) or hypoglossal nerve 
(tongue deviation).   
Xerostomia 
Injury to the submandibular gland as evidenced by the 
subjective decrease in saliva production. 
Contour Irregularity 
Significant indentation or contour irregularity in the treatment 
area that would require surgical intervention. 
Allergic/Irritant Contact 
Dermatitis 
Itchy rashes and skin peeling that may result from prolonged 
exposure to gel or applicator pressure 
Subcutaneous Induration 
Hardness within the treatment area, either as general firmness 
or discrete nodules.  May present with pain and/or discomfort. 
Paradoxical Hyperplasia 
Visibly enlarged tissue volume within the treatment area 
which may develop 2-5 months after treatment. Surgical 
intervention may be required. 
Other 
Any other untoward medical event determined by the 
investigator to be an adverse event, regardless of the 
relationship to the device or treatment. 
 
 
KYBELLA®  
 
• KYBELLA® is contraindicated in the presence of infection at the injection sites. 
 
• Marginal mandibular nerve injury 
Cases of marginal mandibular nerve injury, manifested as an asymmetric smile or facial 
muscle weakness (paresis), were reported during clinical trials. To avoid the potential for 
nerve injury, KYBELLA® should not be injected into or in close proximity to the marginal 


ZELTIQ Aesthetics – Confidential and Proprietary  
 
 
Part Number: 
 Revision: 01 
Page 45 of 46 
Title: Fat Reduction in the Submental Area – A Sequential Treatment Approach 
with CoolMini and KYBELLA® 
 
 
ZELTIQ P/N: 
Protocol Number: ZA17-005 
 
This document and the contents hereof are considered proprietary and confidential information of ZELTIQ Aesthetics, 
Inc.  Disclosure to unauthorized individuals or dissemination, publication or copying is prohibited without prior written consent 
of ZELTIQ. 
mandibular branch of the facial nerve. All marginal mandibular nerve injuries reported from 
the trials resolved spontaneously (range 1-298 days, median 44 days). 
 
• Dysphagia 
Difficulty swallowing (dysphagia) occurred in clinical trials in the setting of administration 
site reactions, e.g., pain, swelling, and induration of the submental area. Cases of dysphagia 
spontaneously resolved (range 1-81 days, median 3 days). Subjects with current or prior 
history of dysphagia were excluded from clinical trials. Avoid use of KYBELLA® in these 
patients as current or prior history of dysphagia may exacerbate the condition. 
 
• Injection site hematoma/bruising 
In clinical trials, 72% of subjects treated with KYBELLA® experienced injection site 
hematoma/bruising. 
 
KYBELLA® should be used with caution in patients with bleeding abnormalities or who are 
currently being treated with antiplatelet or anticoagulant therapy as excessive bleeding or 
bruising in the treatment area may occur. 
 
• Risk of injecting in proximity to vulnerable anatomic structures. To avoid potential tissue 
damage, KYBELLA® should not be injected into or in close proximity (1-1.5 cm) to salivary 
glands, lymph nodes and muscles. 
 
• Injection site alopecia:  withhold subsequent treatments until resolution. 
 
• Injection site ulceration and necrosis:  do not administer to the affected area until complete 
resolution. 
 
Adverse Reactions 
 
In clinical trials, the most commonly reported adverse reactions (≥ 2%) in KYBELLA®-treated 
subjects were: 
 
• 
Injection site reactions including edema/swelling, hematoma/bruising, pain, numbness, 
erythema, induration, paresthesia, nodule, pruritus, skin tightness, site warmth and nerve 
injury; headache, oropharyngeal pain, hypertension, nausea and dysphagia.  
 
• Other adverse reactions associated with the use of KYBELLA® include: injection site 
hemorrhage, injection site discoloration, pre-syncope/syncope, lymphadenopathy, injection 
site urticaria and neck pain. 
 


ZELTIQ Aesthetics – Confidential and Proprietary  
 
 
Part Number: 
 Revision: 01 
Page 46 of 46 
Title: Fat Reduction in the Submental Area – A Sequential Treatment Approach 
with CoolMini and KYBELLA® 
 
 
ZELTIQ P/N: 
Protocol Number: ZA17-005 
 
This document and the contents hereof are considered proprietary and confidential information of ZELTIQ Aesthetics, 
Inc.  Disclosure to unauthorized individuals or dissemination, publication or copying is prohibited without prior written consent 
of ZELTIQ. 
• 
Adverse reactions that lasted more than 30 days and occurred in more than 10% of subjects 
were injection site numbness (42%), injection site edema/swelling (20%), injection site pain 
(16%), and injection site induration (13%).