Premaxillary Injection for Perioral Rejuvenation and Upper Lip Enhancement
Phase: NA
Conditions: Perioral Rejuvenation, Upper Lip Projection
Sponsor: DeNova Research

 
Premaxillary Injection 
Version 2 July, 2017 
 
                                                            Confidential                                                             Page 1 of 18 
 
 
STUDY PROTOCOL 
PROTOCOL TITLE:  
Premaxillary injection for perioral rejuvenation and upper lip 
enhancement 
 
COSMECEUTICAL: 
Restylane® Defyne 
 
SPONSOR:  
 
Steven H. Dayan, M.D., F.A.C.S 
 
INVESTIGATOR: 
Steven H. Dayan, M.D., F.A.C.S 
 
845 North Michigan Avenue, Ste 923E 
                                                Chicago, IL 60611 
                                                Tel: (312) 335-2070 
 
 
 
 
 
 
 
PROTOCOL NUMBER: 
 
 
REST-DEF-2017 
PROTOCOL VERSION DATE: 
 
Version 2, July 12, 2017 
 
NCT NUMBER: 
 
 
03273543 
 
PROTOCOL AUTHOR: 
 
 
Eric W. Cerrati, M.D. 
INVESTIGATIVE SITE: 
 
 
DeNova Research 
 
 
 
845 North Michigan Avenue, Ste 923E 
 
 
 
Chicago, IL 60611 
 
 
 
Tel: (312) 335-2070 
 
 
 
Fax: (312) 335-2074  
 
 
 
CONFIDENTIALITY STATEMENT 
This study is confidential in nature. All information related to this study is considered proprietary and should not be made 
available to those not directly involved in this study. Authorized recipients of this information include investigators and co-
investigators, other health care personnel necessary to conduct the study and institutional review boards. The above 
personnel provided with data from this study are hereby informed of its confidential and proprietary nature.  
 
 
 

 
Premaxillary Injection 
Version 2 July, 2017 
 
                                                            Confidential                                                             Page 2 of 18 
 
 
 
INVESTIGATOR AGREEMENT 
I have read the foregoing protocol and agree that it contains all necessary details for carrying out 
this study. I will conduct the study as outlined herein and will complete the study within the time 
designated. 
I will comply with Good Clinical Practice (GCP) regulations and guidelines during the conduct 
of this study. I certify that this study will be conducted in accordance with the ethical principles 
that have their origin in the Declaration of Helsinki and that they are consistent with Good 
Clinical Practice and applicable regulatory requirements. The study must be conducted in 
accordance with the regulations of the United States Food and Drug Administration (FDA) as 
described in 21 CFR 50 and 812, applicable laws and the IRB requirements. 
I will provide copies of the protocol and all pertinent information to all individuals responsible to 
me who assist in the conduct of this study. I will discuss this material with them to ensure they 
are fully informed regarding the treatment and the conduct of the study. 
I will use only the informed consent form approved by the Institutional Review Board (IRB) or 
Ethics Committee (EC), and will fulfill all responsibilities for submitting pertinent information 
especially with respect to development of any serious adverse events to the Institutional Review 
Board or Ethics Committee responsible for this study. 
 
_____________________________________ 
 
 
______________________ 
 
 
 
 
 
 
 
 
 
 
 
 
Principal Investigator’s Signature 
 
 
 
 
Date 
 
___845 N Michigan Ave______________  
 
___Suite 923 E_____________________  
 
____Chicago, IL 60611_______________  
 
 
 
 
 
 
Address of Principal Investigator (Typed or Printed) 
 
 

 
Premaxillary Injection 
Version 2 July, 2017 
 
                                                            Confidential                                                             Page 3 of 18 
 
 
1 
PROTOCOL SYNOPSIS 
TITLE:  
Premaxillary injection for perioral rejuvenation and upper lip enhancement 
 
INDICATION: 
Premaxillary injection preformed via cannula technique for perioral rejuvenation 
 
SAMPLE SIZE: 
20 
 
NUMBER OF CENTERS: 
One 
 
PURPOSE: 
To determine if subjects who receive premaxillary injection demonstrate an increase in nasal tip 
projection and an associated increase in upper lip projection, and vermillion height. 
 
SUBJECTION SELECTION:     
A total of 20 subjects who display signs of perioral aging or poor upper lip projection 
 
PROCEDURE: 
This is an open-label, prospective, post market study to assess the effect of premaxillary 
hyaluronic acid filler injection on nasal tip projection and upper lip position. 
 
The study will enroll and treat a total of 20 subjects who are filler naïve and do not have any 
history of rhinoplasty, recent upper lip augmentation <12 months, lip lift or other surgical 
procedures involving the upper lip, chin augmentation and orthognathic surgery. Patients in 
study are restricted from perioral neurotoxin, peri oral ablative resurfacing, facial cosmetic 
surgery, all subdermal directed aesthetic treatments or filler treatment other that which is dictated 
in the protocol during the course of the study. 
  
Subjects, who fulfill all eligibility criteria, will undergo pre-treatment standardized 2D portrait 
photography.  From the profile image, baseline nasal projection measurements will be 
documented according to Goode’s ratio.  Additionally, baseline upper lip position will recorded 
by measuring the Z-angle, which is the intersection of the Frankfort horizontal line and the 
profile line as described by Merrifield.  From the straight portrait image, the ratio of the upper lip 
vermillion height to the lower lip vermillion height will be documented.  Subjects will then be 
injected with a maximum of 4 syringes of Restylane® Defyne to treat their premaxillary space 
per the discretion of the Principal Investigator (PI).  If optimal correction result (OCR) has not 
been achieved additional touch-up injections of Restylane® Defyne may be injected 2 weeks 
post treatment visit to achieve OCR as per PI discretion. 

 
Premaxillary Injection 
Version 2 July, 2017 
 
                                                            Confidential                                                             Page 4 of 18 
 
 
 
Post OCR visits will be performed at 4 weeks following premaxillary injections.  Subjects will 
be followed to assess any treatment-related adverse events (such as pain, nodules, swelling, 
redness, bruising, tenderness, itching, and headache) as well as pigmentation changes and/or 
keloid formation.  Each subject will then be photographed with standardized photographs in a 
similar fashion as pre-treatment and the same measurements will be recorded. 
 
Upon study culmination, pre-treatment and 1-month post OCR photographs will be assessed.  
Each patient will be evaluated to determine if nasal tip projection was increased causing an 
increase in upper lip projection.  Additionally, the vermillion ratios will be compared to evaluate 
for change in upper lip vermillion height. 
 
STUDY DURATION: 
Each subject will undergo screening assessment of eligibility criteria, pre-treatment photography, 
and if eligible for treatment, injections of the premaxillary area.  All enrolled subjects will be 
followed up to 1-month post OCR visit to evaluate the injections effect on nasal tip projection 
and upper lip projection. 
 
OBJECTIVES: 
 
The Primary Objective of this study is to determine the increase in nasal tip projection 
(measured by Goode’s ratio) and the increase in upper lip projection (measured by the Z-angle) 
following perioral rejuvenation with premaxillary hyaluronic acid filler injections.  
 
The Secondary Objective of this study is to assess the change in upper lip height by comparing 
the pre and post-treatment injection ratio of upper lip vermillion height to lower lip vermillion 
height.   
 
CLINICAL HYPOTHESES: 
Subjects who are treated with premaxillary injection will demonstrate an increase in nasal tip 
projection and have an associated increase in upper lip projection.  Additionally, the upper lip 
will demonstrate an increase in upper lip vermillion height.  As a result, the single injection site 
will address multiple factors that contribute to perioral aging.  
2 
BACKGROUND   
Earlier this year, Cerrati and Dayan demonstrated the causal relationship between nasal tip 
projection and upper lip projection.  This new correlation, which was discovered in examining 
post-surgical rhinoplasty patients, was published last month in JAMA Facial Plastic Surgery.  As 
the nasal tip was projected, a statistically significant increase in the upper lip projection was 

 
Premaxillary Injection 
Version 2 July, 2017 
 
                                                            Confidential                                                             Page 5 of 18 
 
 
measured.  For tip projection, Goode’s ratio was used.  This value is defined as the nasal height 
over the nasal length.  Upper lip projection was measured by the Z-angle, which is created by the 
Frankfort horizontal plane and the profile line.  A change in the angle to a more acute value on 
postoperative photographs would indicate an increase in upper lip projection.  Additionally, the 
study demonstrated a trend toward an increase in upper lip vermillion height.  By applying this 
new correlation, Dayan was able to recreate the findings in a small subset of aging patients using 
hyaluronic acid filler. 
While the perioral aging process has been well described in the literature, the treatment options 
have remained limited.  The most common attempt at rejuvenation is injection of hyaluronic acid 
filler into the lips and philtral columns.  However, studies have shown that changes occur at 
deeper levels.  Within the orbicularis oris muscle, the curvature relaxes resulting in an overall 
increase in lip length.  More importantly, selective bony resorption occurs in specific areas of the 
facial skeleton including the maxilla.  The retrusion of the maxilla along with widening of the 
piriform aperture contribute to the overlying soft tissue changes in the nose. 
The premaxillary injection adds a new tactic for addressing perioral aging.  The single injection 
will allow treatment of the fundamental cause of aging by re-building the foundation of the face.  
Treatment will provide patients with nature appearing facial rejuvenation.  Since the aging 
process affects both the nose and the upper lip, these patients receive a significant benefit, both 
aesthetically and cost-effectively. 
3 
STUDY OBJECTIVES 
The Primary Objective of this study is to determine the increase in nasal tip projection 
(measured by Goode’s ratio) and the increase in upper lip projection (measured by the Z-angle) 
following perioral rejuvenation with premaxillary hyaluronic acid filler injections.  
 
The Secondary Objective of this study is to assess the change in upper lip height by comparing 
the pre and post-treatment injection ratio of upper lip vermillion height to lower lip vermillion 
height.   
4 
INVESTIGATOR 
Steven H. Dayan, MD, FACS 
845 N. Michigan Ave, Ste 923E 
Chicago, IL 60611 
Tel: 312.335.2070 
Fax: 312.335.2074 

 
Premaxillary Injection 
Version 2 July, 2017 
 
                                                            Confidential                                                             Page 6 of 18 
 
 
5 
STUDY DESIGN 
This is an open-label, prospective, postmarket study to assess the effect of premaxillary 
hyaluronic acid filler injection on nasal tip projection and upper lip position. 
 
The study will enroll and treat a total of 20 subjects who are filler naïve and do not have any 
history of rhinoplasty, recent , 6 months upper lip augmentation, lip lift or other surgical 
procedures involving the upper lip, chin augmentation and orthognathic surgery. Patients in 
study are restricted from perioral  neurotoxin or ablative resurfacing, facial cosmetic surgery, all 
subdermal directed aesthetic treatments or filler treatment other that which is dictated in the 
protocol during the course of the study. 
  
Subjects, who fulfill all eligibility criteria, will undergo pre-treatment standardized 2D portrait 
photography.  From the profile image, baseline nasal projection measurements will be 
documented according to Goode’s ratio.  Additionally, baseline upper lip position will recorded 
by measuring the Z-angle, which is the intersection of the Frankfort horizontal line and the 
profile line as described by Merrifield.  From the straight portrait image, the ratio of the upper lip 
vermillion height to the lower lip vermillion height will be documented.  Subjects will then be 
injected with a maximum of 4 syringes of Restylane® Defyne to treat their premaxillary space 
per the discretion of the Principal Investigator (PI).  If optimal correction result (OCR) has not 
been achieved additional touch-up injections of Restylane® Defyne may be injected 2 weeks 
post treatment visit to achieve OCR as per PI discretion. 
 
Post OCR visits will be performed at 4 weeks following premaxillary injections.  Subjects will 
be followed to assess any treatment-related adverse events (such as pain, nodules, swelling, 
redness, bruising, tenderness, itching, and headache) as well as pigmentation changes and/or 
keloid formation.  Each subject will then be photographed with standardized photographs in a 
similar fashion as pre-treatment and the same measurements will be recorded. 
 
Upon study culmination, pre-treatment and 1-month post OCR photographs will be assessed.  
Each patient will be evaluated to determine if nasal tip projection was increased causing an 
increase in upper lip projection.  Additionally, the vermillion ratios will be compared to evaluate 
for change in upper lip vermillion height. 
 
 
 
 
 
 

 
Premaxillary Injection 
Version 2 July, 2017 
 
                                                            Confidential                                                             Page 7 of 18 
 
 
6 
SUBJECT SELECTION 
A total of 20 subjects.   
 
All Subjects must comply with the following inclusion and exclusion criteria: 
 
6.1 
Inclusion Criteria 
1. Subjects Age 21 to 70. 
2. Subjects who demonstrate signs of perioral aging or poor upper lip projection. 
6.2 
Exclusionary Criteria 
1. Subjects who plan to undergo peri oral neurotoxin treatments or ablative skin 
treatments, or have had either of these treatments in the previous 6 months, other 
injectable filler treatments during the course of the study. 
2. Subjects who are pregnant or nursing. 
3. Subjects with a known allergy or sensitivity to any component of the study 
ingredients. 
4. Any history of nasal filler injections. 
5. Recent history of upper lip augmentation (surgical and non-surgical) within the 
last 12 months. 
6. Any history of lip lift or other surgical procedures involving the upper lip. 
7. Any history of chin augmentation (surgical and non-surgical). 
8. Any history of orthognathic surgery. 
9. Any history of bleeding disorders (iatrogenic or otherwise). 
10. Current history of chronic drug or alcohol abuse. 
11. Concurrent therapy that, in the investigator’s opinion, would interfere with the 
evaluation of the safety or efficacy of the study product (i.e. immunosuppressive 
therapy). 
12. Subjects who, in the Investigator’s opinion, have a history of poor cooperation, 
noncompliance with medical treatment or unreliability. 
7 
TREATMENT AND STUDY MATERIAL SUPPLIES 
 
7.1 
Description of Study Supplies and Handling 
7.1.1 Packaging and Labeling 
 
 
7.1.1.1 Restylane® Defyne 
Injectable Gel with 0.3% Lidocaine 
2.1.2 Method of Application 
Pre-treatment Guidelines 

 
Premaxillary Injection 
Version 2 July, 2017 
 
                                                            Confidential                                                             Page 8 of 18 
 
 
Prior to treatment, the patient should avoid taking aspirin, nonsteroidal anti-
inflammatory medications, St. John’s Wort, or high doses of Vitamin E 
supplements. These agents may increase bruising and bleeding at the injection 
site. 
Treatment Procedure 
1. It is necessary to counsel the patient and discuss the appropriate indication, 
risks, benefits and expected responses to the Restylane® Defyne treatment.  
Advise the patient of the necessary precautions before commencing the 
procedure. 
2. Assess the patient’s need for appropriate anesthetic treatment for managing 
comfort, i.e., topical anesthetic, local or nerve block. 
3. The patient’s face should be washed with soap and water and dried with a clean 
towel. Cleanse the area to be treated with alcohol or another suitable antiseptic 
solution. 
4. Sterile gloves are recommended while injecting Restylane® Defyne. 
5. Attach the syringe to a 22-gauge cannula, which provides additional safety 
when injecting in this area.  Before injecting, press rod carefully until a small 
droplet is visible at the tip of the cannula. 
6. Using a 20-gauze needle, a small access point is created for the cannula.  The 
access points are located within the superior portion of the nasolabial folds 
bilaterally 
7. Inject Restylane® Defyne applying even pressure on the plunger rod. It is 
important that the injection is stopped just before the cannula is pulled out of the 
skin to prevent material from leaking out or ending up too superficially in the 
skin.   
8. Only correct to 100% of the desired volume effect. Do not overcorrect. The 
degree and duration of the correction depend on the character of the defect 
treated, the tissue stress at the implant site, the depth of the implant in the tissue 
and the injection technique. 

 
Premaxillary Injection 
Version 2 July, 2017 
 
                                                            Confidential                                                             Page 9 of 18 
 
 
9. Typical usage for each treatment session is specific to the amount of correction 
desired.  
Injection Techniques 
1. Restylane® Defyne can be injected by a number of different techniques that 
depend on the treating physician’s experience and preference, and patient 
characteristics. 
2. Given the close proximity to large vessels within the premaxillary space, the 
cannula technique is advocated.  The use of large cannulas (22-gauge) helps 
minimize the risk of vascular injury.  The cannulas are introduced through the 
skin by a small puncture site created by a slightly larger hypodermic needle. 
3. Once the cannula is inserted, linear threading (includes retrograde and 
antegrade) is accomplished along with fanning to produce an even layer of 
material.  The material should be deposited in the premaxillary space, which is 
located between the maxilla and the orbicularis oris muscle spanning between the 
alar bases. 
8 
STUDY PROCEDURES 
 
8.1 
Screening Visit 
The PI and/or designee is responsible for keeping a record of all subjects screened for entry into 
the study and those subjects that were excluded, including exclusionary reason. 
 
The following procedures will be performed: 
1. The PI and/or designee is responsible to evaluate and confirm that a subject meets 
inclusionary/exclusionary criteria.  
2. Subjects must provide signed informed consent with confirming signature from 
investigator/site designee. 
3. Subject undergo standard 2D digital portrait photography. 
 
8.2.   Visit 1: Baseline/Treatment Procedures  
The following procedures will be performed: 
1. The injection area will be wiped with a Benzalkonium Chloride towlette. 
2. A topical anesthetic containing lidocaine (30%) will be applied to anesthetize injection 
areas Or subject may choose to receive a nerve block to numb the treatment area. 

 
Premaxillary Injection 
Version 2 July, 2017 
 
                                                            Confidential                                                             Page 10 of 18 
 
 
3. The subject will be injected with Restylane® Defyne in a volume sufficient to deliver 
satisfactory cosmetic results (not to exceed 4mL/4syringes total). 
4. The volume injected into each area will be recorded. 
 
8.3.  Visit 2: Two Week Touch-up Visit 
The following procedures will be performed: 
1. At PI’s discretion, subjects may receive touch-up treatment to reach Optimal Cosmetic 
Result (OCR) (not to exceed a total use of 4mL/4 syringes of Restylane® Defyne). 
2. Subject will report any AE or Concomitant medications 
 
8.4.  Visit 3: One Month Follow-up Visit 
The following procedures will be performed: 
1. Subject will undergo standardized 2D digital portrait photography.  
 
9 
RESPONSE CRITERIA 
 
 
9.1 
Primary Variable Assessments 
The primary assessment of this study is to determine the effect of premaxillary injection on nasal 
tip projection and upper lip projection for perioral rejuvenation.  Efficacy of the injection on the 
subjects’ 1-month post OCR with Restylane® Defyne will be done through comparative 
measurements taken on pre and post-treatment photographs. 
Nasal tip projection will be assessed by Goode’s ratio.  The value is defined as nasal height over 
the nasal length.  The nasal height is measured from the alar-facial groove to the tip-defining 
point and the nasal length is measured from the root of the nose, or nasion, to the tip-defining 
point.  Upper lip projection will be measured by a method outlined by Merrifield in 1966.  As 
described, a profile line is drawn tangent to the soft tissue chin and to the most anterior point of 
the upper lip.  This line is then extended upward to the Frankfort horizontal plane.  The angle at 
which these two lines intersect is called the Z angle.  A change in the angle to a more acute value 
on postoperative photographs would indicate an increase in upper lip projection.  This method 
was chosen because it is calculated independent of any postoperative nasal changes.  
 
 
 
 
9.2   
Secondary Variable Assessments 
The secondary assessment is to evaluate the change in upper lip height by comparing the pre and 
post-injection ratio of upper lip vermillion height to lower lip vermillion height.  This method 
was chosen because ratios eliminate any bias created by camera distance, angle, lighting, etc. 

 
Premaxillary Injection 
Version 2 July, 2017 
 
                                                            Confidential                                                             Page 11 of 18 
 
 
 
 
 
10 
DATA MANAGEMENT 
 
10.1 
Case Report Forms (CRFs) 
For each subject enrolled who has given informed consent, completed the screening process, and 
began the study process, a CRF will be created and signed by PI or designee to certify 
completeness and correctness. 
 
If a subject is withdrawn from the study due to a treatment-limiting adverse event, due diligence 
must be used to document the outcome. Source documentation verification will be performed by 
the study monitors. All CRFs will remain at the study site. 
 
10.2 
Data Handling 
Data management based on GCP refers to the activities defined to achieve safe routines to enter 
clinical data information into a database, efficiently and avoiding errors. The data management 
routines include procedures for handling CRFs, database set-up and management, data entry and 
verification, data validation, and documentation of the performed activities including information 
of discrepancies in the process. 
 
The database, the data entry screens, and program will be designed in accordance with the study 
protocol and the CRF. Single data entry and proofreading will be used for data entry and 
verification. Data validation will be performed after data entry and verification by manual review. 
When the clinical study coordinator has made all efforts to ensure that the data recorded in the 
CRFs and entered in the database is as correct and complete as possible, "clean file" is declared, and 
the database is closed. The clinical study coordinator should document the database closure in a 
signed written document. Final statistical analysis should be generated using data from the closed 
database. Any additional subsequent changes or corrections to the closed database should be 
documented in an audit trail. 
11 
STATISTICAL METHODS 
 
11.1 
Study Populations 
The study population will include all subjects who are enrolled, and the entire study population 
will be included in statistical analyses. 
 
11.2  
Study Endpoints 
The endpoint is a comparative analysis of pre and post-treatment photographs.  Measurements 
and calculation will be performed based off of the portrait and profile images.  

 
Premaxillary Injection 
Version 2 July, 2017 
 
                                                            Confidential                                                             Page 12 of 18 
 
 
 
 
       11.3  
Analysis Method  
The PI’s study coordinator will perform all statistical analyses.  This is in an effort to avoid any 
potential bias that could be created by the treating physician participating in the analysis.  Given 
that there is inherent variability even in standardized portrait photography, the decision was 
made to perform measurements based on facial landmarks and distance ratios.  Statistical 
analysis will be conducted using a paired t test. 
12 
ADVERSE EVENT  
 
12.1 
Definition 
An adverse event is defined as any untoward medical occurrence in a subject or clinical 
investigation subject administered a pharmaceutical or medical device product that does not 
necessarily have a causal relationship with this treatment. Adverse events include the following: 
all suspected adverse device or procedure reactions, occurrence of apparently unrelated illnesses 
(i.e., symptoms or diseases that were not present at study entry), worsening of a pre-existing 
illness (i.e., concurrent symptoms or diseases), injuries or accidents, or abnormalities in 
physiological or laboratory testing or physical examination findings that require clinical 
intervention or further investigation (beyond ordering a repeat confirmatory test).  Throughout the 
study, subjects will be monitored for signs and symptoms of adverse events.   
 
All adverse events reported during the study period will be recorded in detail in the subject’s 
medical file and CRF. 
 
12.2 
Recording of Adverse Event 
Subjects will be instructed by the PI to immediately report the occurrence of any adverse event. 
Each subject should be questioned at all visits whether any side effects or adverse events have 
occurred. All spontaneously volunteered, inquired, and observed adverse experiences will be 
recorded in detail. 
 
12.3 
Serious Adverse Events (SAE) and Unanticipated Adverse Device Effects 
 
12.3.1 
Definitions 
Serious Adverse Events (SAEs) are defined as undesirable events experienced by a subject that 
suggest a significant hazard, contraindication, side effect, or precaution, whether or not 
considered to be device-related by the Investigator. An AE is defined as being serious if: 
1. It is fatal or life threatening (life threatening means that in the opinion of the Investigator, 
the subject was at immediate risk of death from the adverse reaction). 
2. It is permanently or temporarily disabling. 
3. It requires inpatient or prolonged hospitalization. 

 
Premaxillary Injection 
Version 2 July, 2017 
 
                                                            Confidential                                                             Page 13 of 18 
 
 
4. Is a congenital anomaly/birth defect. 
 
An unanticipated adverse device effect is defined as any serious adverse effect on health or 
safety, any life threatening problem, or death was not previously identified in nature, severity, or 
degree of incidence in the investigational plan or application (including a supplementary plan or 
application), or any other unanticipated serious problem associated with a device that relate to 
the rights, safety, or welfare of subjects. 
 
12.3.2 
Serious Adverse Event (SAE) Recording and Reporting 
Any serious and/or unexpected adverse event that occurred while on study or one month after 
completion of study must be reported to DeNova Research via telephone and the Serious 
Adverse Event Report Form must be completed and faxed to DeNova Research and IRB within 
24 hours of notification. 
  
In addition, the local IRB (Institutional Review Board) or ERC (Ethics Review Committee) must 
be notified of all adverse events that are serious and/or unexpected.   
 
All adverse events, including serious and unexpected events, must be recorded by the 
Investigator on the standard Adverse Event Report. This form will be included in the CRF. All 
Adverse Event Reports describing adverse events other than serious or unexpected adverse 
events will be inserted into the CRF. In addition, any serious and treatment-related unexpected 
adverse events must be reported to the local IRB (Institutional Review Board) within 5 business 
days of the event.  
 
Subjects who have had a serious adverse event must be followed clinically until all parameters, 
including laboratory values, have either returned to normal, or are otherwise explained. If death 
was the outcome of the event on the initial Adverse Event Report, a Follow-up/Final Report, 
including autopsy report, when performed, must be completed. 
13 
QUALITY ASSURANCE 
 
13.1 
Institutional Review Board Approval 
An IRB shall review and have authority to approve, require modifications in, or disapprove the 
investigation. Accordingly, this protocol, the informed consent document, and any relevant 
supporting information must be submitted to the IRB for review and receive approval prior to 
study initiation. Except in an emergency, any amendments to the protocol require approval by 
both Sponsor and the IRB prior to their implementation. 
 

 
Premaxillary Injection 
Version 2 July, 2017 
 
                                                            Confidential                                                             Page 14 of 18 
 
 
Additionally, the PI is responsible for providing the IRB with progress reports of the 
investigation at regular intervals (at least once per year), as well as with any other accurate, 
complete, and current information that the IRB may request concerning the investigation. 
 
13.2 
Informed Consent 
Informed consent shall be documented by the use of a written consent form approved by the IRB 
and signed by the subject or the subject’s legally authorized representative. A copy of the final, 
IRB-approved document must be provided for record-keeping purposes. Originals of the IRB-
approved consent form and sign individual consent documents must be retained in the site’s 
study files. Each subject must be provided with a copy of his/her signed consent form. 
 
 
13.3 
Study Monitoring 
The PI will allow designees from the study sponsor to periodically audit all CRFs and 
corresponding source documents for each subjects, as well as, any data related to the study file. 
The monitoring visits provide for an opportunity to evaluate the progress of the study, to verify 
the accuracy and completeness of CRFs, to resolve any inconsistencies in the study records, and 
to assure that all protocol requirements, applicable regulations, and Investigator’s obligations are 
being met. The PI must maintain source documents such as lab reports, photographs, history, and 
physical examination reports, etc., for possible review. 
 
13.4 
Modification of Protocol 
If modification of the protocol is necessary, the modification must be confirmed with the IRB. 
No change to the protocol that significantly affects the safety, scope, or quality of the study may 
be implemented prior to written approval of the IRB. However, changes to the protocol may be 
made when necessary for the health of the subject. All modifications must be documented at the 
site. Moreover, if the study protocol is revised at any point during the study, IRB will be notified 
according to CRF 21 Part 812. 
 
13.5 
Departure from the Protocol 
Minor deviations to the study protocol may be permitted if they will not increase the subject’s 
risk or affect the validity of the study. All deviations must be documented at the study site. 
 
When an emergency occurs that requires a departure from the protocol for an individual, a 
departure will be only for that subject. The PI in such an emergency will, if circumstances and 
time permit, contact the IRB prior to departing from the protocol. If this is not possible, such 
contact must be made as soon as possible, to allow an evaluation of the significance of such 
departure to the affected subject and to other subjects, and to permit a decision as to whether or 
not the subject (for whom the departure from the protocol was affected) is to continue in the 
study. The CRFs will completely describe the departure from the protocol and state the reasons 
for such departure. In addition, IRB will be notified in writing of such departure from protocol. 

 
Premaxillary Injection 
Version 2 July, 2017 
 
                                                            Confidential                                                             Page 15 of 18 
 
 
 
13.6 
Confidentiality of Subject Records 
The information obtained during the conduct of this study is confidential, and will be disclosed 
only to the Investigator and regulatory authorities as deemed necessary and/or as required by 
law. The PI must provide full disclosure of all study data and make study files available for 
inspection upon request by the IRB and/or relevant authorities including the study sponsor. Upon 
notice, the local authorizes may inspect and copy records that identify subjects through number 
and initial combinations. However, such copies have to be blinded (i.e., all personally 
indentifying data have to be blacked out) in order to prevent identification. The sponsor will be 
notified of any impending inspections relating to the study 
 
13.7 
Record Retention 
The PI shall maintain accurate, complete, and current records relating to the participation in this 
study, including the following: 
1. All correspondence including required reports. 
2. Records of device shipment and disposition. 
3. Signed Investigator Agreements. 
4. The protocol and any protocol amendments. 
5. Records concerning adverse events whether anticipated or not. 
6. Documentation of each subject’s case history and exposure to the device, including any 
CRFs, signed and dated consent forms, and any relevant medical records. 
7. Any other records that the applicable authorities require to be maintained by regulation or 
by specific requirement for a particular device or category of devices. 
 
The PI shall maintain all detailed essential documents for the duration of the investigation and 
for a period of at least 2 years since the formal discontinuation of clinical development of the 
investigational product, or 2 years after the last approval of any marketing application, or as 
required by the applicable regulatory requirements, whichever of them is a longer period.  
 
13.8 
Additional Principal Investigator Responsibilities 
The PI is responsible for protecting the rights, safety, and welfare of subjects under his/her care. 
The PI is responsible for ensuring that the study is conducted according to the signed agreement 
with the investigational protocol, applicable regulations, and any condition of approval imposed 
by the IRB.   
 

 
Premaxillary Injection 
Version 2 July, 2017 
 
                                                            Confidential                                                             Page 16 of 18 
 
 
14        Appendices 
 
Appendix A:  Photography Standardization  
Appendix B:  Diagram of planned measurements 
 
 

 
Premaxillary Injection 
Version 2 July, 2017 
 
                                                            Confidential                                                             Page 17 of 18 
 
 
Appendix A:  Photo SOP 
Photography and Poses 
• 
Use the grid feature on any of these viewers to ensure the Frankfort Plane (imaginary line 
from tragus to infraorbital rim) is parallel to the floor 
• 
Stand approximately 1.5m from patient with the camera in a portrait position. The 
location will be marked on the floor of the photography studio. 
• 
Ensure the patient has a relaxed expression and that their lips are closed and eyes are 
open for each photo. 
• 
Give instructions like, “Slowly move you’re your chin down” or “Slowly turn your nose 
to the left” to achieve the desired poses listed below 
 
Standard Poses (all @ 1.5 m) 
1. Frontal 
a. Make sure the patient doesn’t have their chin high or low by checking the 
Frankfort Plane. For this view, the line on the viewfinder should extend from the 
right tragus, across both infraorbital rims and across the left tragus. This should be 
parallel to the floor 
2. Left Profile 
a. For this view, ensure the patient is not rotated to the left or right (hint: look at the 
eyebrows to see how much of the glabella you see).  
2. Right Profile 
a. For this view, ensure the patient is not rotated to the left or right (hint: look at the 
eyebrows to see how much of the glabella you see). 
 

 
Premaxillary Injection 
Version 2 July, 2017 
 
                                                            Confidential                                                             Page 18 of 18 
 
 
Appendix B:   Measurements