A Randomized, Double-masked, Active Controlled, Within-subject Equivalency Clinical Trial to Compare Effectiveness and Safety of Lunaphil Ultra (Hyaluronic Acid, Produced by Espad Pharmed Co.) Versus Juvederm Ultra 4® (Hyaluronic Acid, Produced by Allergan Co.) for the Management of Moderate or Severe Nasolabial Folds
Phase: NA
Conditions: Moderate or Severe Nasolabial Folds
Sponsor: Espad Pharmed

1 
 
 
A Post-Authorization Safety (and Effectiveness) Study Protocol  
Title 
A randomized, double-masked, active controlled, within-subject 
equivalency clinical trial to compare effectiveness and safety of Lunaphil 
Ultra (Hyaluronic acid, produced by Espad Pharmed Co.) versus Juvederm 
Ultra 4® (Hyaluronic acid, produced by Allergan Co.) for the management 
of moderate or severe nasolabial folds  
Date 
14/08/2021 
IRCT register number 
Not Applicable 
Active substance 
Hyaluronic acid (M09AX01)  
Medicinal product 
Hyaluronic acid (Lunaphil Ultra®) 
Product reference 
Juvederm Ultra 4® 
Procedure number 
Not Applicable 
Joint PASS 
No 
Research question and objectives 
This study aims to assess the safety and effectiveness of Lunaphil Ultra for 
the management of moderate or severe nasolabial folds (NLFs) 
Country(-ies) of study 
Iran 
Author 
Dr. Kamran Balighi 
Department of Dermatology, Razi Hospital, Tehran University of Medical 
Sciences, Tehran, Iran. 
 
 
 
 
 

2 
 
Table of Contents 
 
1 
List of Abbreviations ............................................................................................................................................ 4 
2 
Responsible Parties ............................................................................................................................................... 4 
2.1 
Principal Investigator ................................................................................................................................... 4 
3 
Other responsible parties ....................................................................................................................................... 5 
3.1 
Sponsor ........................................................................................................................................................ 5 
3.1.1 
Sponsor representatives for audition to ensure the quality of study conduct: .......................................... 6 
4 
Abstract ................................................................................................................................................................. 9 
5 
Rationale and Background .................................................................................................................................. 11 
6 
Research Question and Objectives ...................................................................................................................... 11 
7 
Amendments and Updates .................................................................................................................................. 12 
8 
Research Methods ............................................................................................................................................... 12 
8.1 
Study Design .............................................................................................................................................. 12 
8.2 
Setting ........................................................................................................................................................ 12 
8.2.1 
Subjects .................................................................................................................................................. 12 
8.3 
Study Timeline ........................................................................................................................................... 14 
8.4 
Variables .................................................................................................................................................... 15 
8.5 
Data Sources and Measurement ................................................................................................................. 15 
8.6 
Study Size .................................................................................................................................................. 15 
8.7 
Statistical Methods ..................................................................................................................................... 15 
8.7.1 
Main Summary Measures ...................................................................................................................... 15 
8.7.2 
Main Statistical Methods ....................................................................................................................... 15 
8.8 
Quality Control .......................................................................................................................................... 16 
8.9 
Limitations of the Research Methods ......................................................................................................... 16 
9 
Protection of Human Subjects............................................................................................................................. 16 
10 
Management and Reporting of Adverse Events/Adverse Reactions ................................................................... 16 
11 
Plans for Disseminating and Communicating Study Results .............................................................................. 18 

3 
 
12 
References ........................................................................................................................................................... 18 
13 
Appendices.......................................................................................................................................................... 19 
 
 
 

4 
 
1 
List of Abbreviations   
Table 1-1. List of abbreviations 
Abbreviation 
Description 
ADL 
Activities of Daily Living 
ADR 
Adverse Drug Reaction 
AE 
Adverse Event 
CRF 
Case Report Form 
CTCAE 
Common Terminology Criteria for Adverse Events 
GCP 
Good Clinical Practice 
HA 
Hyaluronic Acid 
ICH 
International Council for Harmonization of Technical Requirements for Pharmaceuticals 
MedDRA 
Medical Dictionary for Regulatory Activities 
NLF 
Nasolabial Fold 
NSAID 
Non-Steroidal Anti-Inflammatory Drug 
OTC 
Over-the-Counter 
PGAIS 
Physician Global Aesthetic Improvement Scale 
PMS 
Postmarketing Surveillance 
PT 
Preferred Term 
SOC 
System Organ Class 
SOP 
Standard Operating Procedure 
WHO 
World Health Organization 
WSRS 
Wrinkle Severity Rating Scale 
 
2 
Responsible Parties   
Roles and Responsibilities:  
• 
Conducting the study according to the agreed protocol, International Council for Harmonization and good 
clinical practice (GCP) guidelines  
• 
Selecting study team and ensuring adequate training and familiarity with the roles 
• 
Organizing training sessions for existing and newly recruited team members whenever necessary 
• 
Supervising and approval of suitable places for participant visit 
• 
Cooperation with monitors during the conduction of the study 
 
 
 
 
2.1 
Principal Investigator

5 
 
 
Name: Dr. Kamran Balighi 
Affiliation: Department of Dermatology, Razi Hospital, Tehran University of Medical Sciences, Tehran, Iran. 
Participant recruitment site: No 42, Attar Sq., Attar St, Valiasr Ave., Vanak Sq., Tehran, Iran 
Signature:  
 
 
 
 
Names:  
Names of investigators are presented in Table 2-1Error! Reference source not found.. 
Table 2-1. Names of investigators 
Investigators 
Dr. Kamran Balighi 
Dr. Kamran Jazayeri 
Dr. Omid Zargari 
 
3 
Other responsible parties   
Roles and Responsibilities: 
• 
Study protocol preparation 
• 
Preparing CRFs 
• 
Obtaining necessary approvals from external organizations for conducting the study 
• 
Providing SOP for the investigators in study centers 
• 
Funding provision for site staffs collaborating in data collection via signing contracts with the chief and principal 
investigators 
• 
Providing necessary training for the staff 
• 
Recruiting necessary workforce to conduct monitoring of the trial and the data management 
• 
Planning and conducting statistical analyses. 
3.1 
Sponsor 

6 
 
• 
Preparing required study reports. 
 
Name: Dr. Araz Sabzvari (Espad Pharmed Co. representative) 
Address: Orchid Pharmed Co, No. 42, Attar square, Vanak street, Tehran, Iran. 
Tel: +9843473000 
Hotline: +9843473600 
 
 
3.1.1 
Sponsor representatives for audition to ensure the quality of study conduct: 
 
Name: Dr. Hamidreza Kafi (Pharmacotherapy Specialist), Medical Manager, Orchid Pharmed Co. 
Address: Orchid Pharmed Co, No. 12, 70th. Alley, Seyed Jamaledin Asad Abadi St., Yousef Abad, 
Tehran, Iran. 
Tel: +982143473000 
Hotline: +982143473000 (4400) 
Signature:  
 
Name: Saghar Barati, Medical Consultant, Orchid Pharmed Co. 
Address: Orchid Pharmed Co, No. 12, 70th. Alley, Seyed Jamaledin Asad Abadi St., Yousef Abad, 
Tehran, Iran. 
Tel: +982143473000 
Hotline: +982143473000 (4491) 
Signature:  
 
Name: Sogol Albooyeh, Clinical Research Manager, Orchid Pharmed Co. 

7 
 
Address: Orchid Pharmed Co, No. 12, 70th. Alley, Seyed Jamaledin Asad Abadi St., Yousef Abad, 
Tehran, Iran. 
Tel: +982143473000 
Hotline: +982143473000 (4420) 
Signature:  
 
Name: Shahriar Ahmadi, Medical Writing Head, Orchid Pharmed Co. 
Address: Orchid Pharmed Co, No. 12, 70th. Alley, Seyed Jamaledin Asad Abadi St., Yousef Abad, 
Tehran, Iran. 
Tel: +982143473000 
Hotline: +982143473000 (4441) 
Signature:  
 
Name: Erfan Ghani, Medical Writing Supervisor, Orchid Pharmed Co. 
Address: Orchid Pharmed Co, No. 12, 70th. Alley, Seyed Jamaledin Asad Abadi St., Yousef Abad, 
Tehran, Iran. 
Tel: +982143473000 
Hotline: +982143473000 (4483) 
Signature:  
 
Name: Mahan Molaei, Medical Writing Specialist, Orchid Pharmed Co. 
Address: Orchid Pharmed Co, No. 12, 70th. Alley, Seyed Jamaledin Asad Abadi St., Yousef Abad, 
Tehran, Iran. 
Tel: +982143473000 

8 
 
Hotline: +982143473000 (4479) 
Signature:  
 
Name: Farzane Jamali, Medical Writing Specialist, Orchid Pharmed Co. 
Address: Orchid Pharmed Co, No. 12, 70th. Alley, Seyed Jamaledin Asad Abadi St., Yousef Abad, 
Tehran, Iran. 
Tel: +982143473000 
Hotline: +982143473000 (4475) 
Signature:  
 
Name: Ramin Shahpari, Health Data Science Manager, Orchid Pharmed Co. 
Address: Orchid Pharmed Co, No. 12, 70th. Alley, Seyed Jamaledin Asad Abadi St., Yousef Abad, 
Tehran, Iran. 
Tel: +982143473000 
Hotline: +982143473000 (4300) 
Signature:  
 
Name: Leila Nezamabadi Farahani, Biostatistician Specialist, Orchid Pharmed Co.  
Address: Orchid Pharmed Co, No. 12, 70th. Alley, Seyed Jamaledin Asad Abadi St., Yousef Abad, 
Tehran, Iran. 
Tel: +982143473000 
Hotline: +982143473(4319) 
Signature:    

9 
 
Name: Newsha Fallah, Pharmacovigilance Manager, Orchid Pharmed Co. 
Address: Orchid Pharmed Co, No. 12, 70th. Alley, Seyed Jamaledin Asad Abadi St., Yousef Abad, 
Tehran, Iran. 
Tel: +982143473000 
Hotline: +982143473000 (4360) 
Signature:  
 
Name: Mohammad Hossein Mirzaei Pharmacovigilance Expert, Orchid Pharmed Co. 
Address: Orchid Pharmed Co, No. 12, 70th. Alley, Seyed Jamaledin Asad Abadi St., Yousef Abad, 
Tehran, Iran. 
Tel: +982143473000 
Hotline: +982143473000 (4366) 
Signature:  
 
4 
 Abstract  
Title  
A randomized, double-masked, active-controlled, within-subject equivalency clinical trial to compare effectiveness 
and safety of Lunaphil Ultra (Hyaluronic acid, produced by Espad Pharmed Co.) versus Juvederm Ultra 4® 
(Hyaluronic acid, produced by Allergan Co.) for the management of moderate or severe nasolabial folds (NLFs) 
 
Dr. Kamran Balighi 
Department of Dermatology, Razi Hospital, Tehran University of Medical Sciences, Tehran, Iran 
Keywords  
Lunaphil Ultra, Hyaluronic Acid, Nasolabial Folds 
Rationale and Background  
Skin aging is a complex process that results in various changes in the skin, including wrinkles, sun spots, and sagging 
skin. The NLF is a natural change that becomes more prominent with aging and significantly affects the beauty of the 

10 
 
facial skin. Dermal fillers, particularly HA fillers, are commonly used to correct these signs of aging. This study aims 
to compare the effectiveness and safety of Lunaphil Ultra with Juvederm Ultra 4® for treating NLFs. 
Research Question and Objectives  
Primary objective: 
Effectiveness assessment of Lunaphil Ultra 
Secondary objectives:  
Effectiveness and safety assessment of Lunaphil Ultra 
Study Design  
This is a randomized, double-masked, active controlled, within-subject, and equivalency clinical trial. 
Setting  
Subjects will be treated with Lunaphil Ultra in one NLF and Juvederm Ultra 4® in the opposite NLF. 
A total of 108 participants will be enrolled in the study. For each participant, the products will be injected in the first 
visit and if needed an additional injection will be done (touch-up) at visit 2 (week 2). The duration of the study is 24 
weeks for each participant. 
Subjects and study size, including drop-outs 
A population of 108 participants will be enrolled in the study, and during 24 weeks, study-related data will be 
collected.  
Variables and Data Sources  
Lunaphil Ultra will be administered over a 2-week period (initial treatment plus one touch-up) to achieve optimal 
correction of the NLFs. 
The primary objective of this study is effectiveness assessment, including the mean level of improvement from 
baseline in NLF severity score by Wrinkle Severity Rating Scale (WSRS) at week 24. 
Variables in this study includes patient demographic information (age, sex), history of filler injection, baseline WSRS 
and subsequent scores at other visits, patient’s medical history, patient’s medications, injection volume, receipt of 
touch-up treatment, Physician Global Aesthetic Improvement Scale (PGAIS) at each visit, and adverse events (AE) 
reporting. 
Name and affiliation of principal investigator  
Dr. Kamran Balighi 
Department of Dermatology, Razi Hospital, Tehran University of Medical Sciences, Tehran, Iran. 
Data Analysis 
The primary endpoint will be assessed by measuring the mean level of improvement from baseline in NLFs severity 
score using either a paired t-test or a signed-rank test. 
The number of patients with an improved score for the PGAIS, proportion of NLFs with clinically significant 
improvement and the number of NLFs receiving touch-up treatment will be analyzed using a McNemar test. Injection 
volume to obtain optimal result will be analyzed with a paired t-test or a signed-rank test. 
The safety data will be analyzed primarily using incidence and frequency. AEs' severity, seriousness, and causality 
assessment will be reported. 

11 
 
5 
Rationale and Background  
Skin aging is a complex and multifactorial process resulting in various functional and aesthetic changes in the skin 
(1). It is an inevitable process that can be described clinically as features of wrinkles, sun spots, uneven skin color, 
and sagging skin (2). Additional clinical findings include tear trough, a drop of the angle of the mouth, loss of 
definition in the mandibular border, platysmal bands, evident veins, and NLFs as one of the typical clinical 
manifestations of facial aging (3).  
The perception of health and age is a critical aspect in the common judgment of attractiveness and people are judged 
to be less attractive as they age (4). Attractiveness influences both self-perception and social behavior and is related 
to traits such as self-confidence and social acceptance. Therefore, aesthetic interventions can improve psychological 
well-being and quality of life (5).  
Dermal fillers are widely used for the correction of deep wrinkles, including NLFs. Treatments with dermal fillers 
provide favorable aesthetic outcomes with minimal invasiveness and no downtime following surgical procedures (6). 
Hyaluronic acid (HA) fillers, the most popular dermal fillers (7), demonstrate desirable effects on the fibroblast 
phenotype, including higher cell proliferation and type I collagen synthesis (8). HA fillers have predictable efficacy, 
a good safety profile, quick recovery, and simplicity in administration (9, 10).   
Different factors, including HA concentration, polymer chain length, and crosslinking degree or technology, influence 
filler properties such as the requisite needle size, particle size, duration, extrusion force, and elastic Modulus (G'). All 
of these factors will critically influence product selection and indication (11). Among these factors, crosslinking is 
essential to slowing down the enzymatic degradation rate of the HA by endogenous hyaluronidase and prolonging the 
product’s half-life. The extent of crosslinking strongly impacts the biophysical and biological properties of a filler, 
including tissue integration, water uptake, resistance to degradation, and filler biocompatibility and consequently 
might have clinical implications (12).  
Lunaphil Ultra intradermal filler is a cross-linked HA soft tissue filler manufactured by Espad Pharmed Company. It 
contains 24 mg/ml of HA and 0.3% lidocaine as a supplemental anesthetic. Since pain is the most commonly reported 
complaint with dermal fillers, a local anesthetic like  lidocaine is included in their formulation to reduce procedural 
pain and bypass the need for additional anesthesia (13).  
The aim of this study is to compare the effectiveness and safety of Lunaphil Ultra (Hyaluronic acid, produced by 
Espad Pharmed Co.) versus Juvederm Ultra 4® (Hyaluronic acid, produced by Allergan Co.) in managing moderate 
or severe NLFs. 
6 
Research Question and Objectives  
Primary objective: 
- 
Mean level of improvement from baseline in NLF severity score by WSRS at week 24  
Secondary objective: 
- 
Number of subjects with an improvement score based on PGAIS at week 24  
- 
Proportion of NLFs maintaining a clinically significant improvement in NLF severity score (≥1-point reduction 
from baseline) at week 24  

12 
 
- 
The injected volume to obtain optimal aesthetic result (initial treatment + touch-up) 
- 
The number of NLFs receiving touch-up treatment 
- 
The incidence, severity and causal relationship of adverse events 
7 
Amendments and Updates   
There are no amendments and updates throughout the study. 
8 
Research Methods  
This is a randomized, double-masked, active controlled, within-subject, and equivalency study to compare the 
effectiveness and safety of Lunaphil Ultra (Hyaluronic acid, produced by Espad Pharmed Co.) versus Juvederm Ultra 
4® (Hyaluronic acid, produced by Allergan Co.) for the management of moderate or severe NLFs. 
8.2.1 
Subjects 
A total of 108 participants with moderate to severe NLFs will be enrolled in the study. 
 
Inclusion Criteria 
• 
Subjects ≥ 30 years of age 
• 
Visible bilateral NLFs that are approximately symmetrical and have an equal severity ranging from moderate to 
severe (assessed at the deepest part) 
• 
Able to follow study instructions and likely to complete all required visits 
• 
Signed informed consent 
 
Exclusion Criteria 
• 
History of bleeding disorders or participants receiving or recently exposed (≤ 3 weeks) to continuous treatment 
with thrombolytics, anticoagulants, platelet inhibitors, or NSAIDs 
• 
Acute herpetic eruption 
• 
Known susceptibility to keloid formation, hypertrophic scarring or clinically significant skin pigmentation 
disorders 
• 
Known sensitivity to local anesthetics of the amide type (such as lidocaine), history of hypersensitivity to gram-
positive bacterial proteins, history of multiple severe allergies, history of anaphylactic shock 
• 
Known hypersensitivity to any component of the study products or excipients (like hyaluronic acid) 
• 
History of receiving immune therapy or a history of autoimmune disease 
• 
History of active chronic debilitating systemic disease 
8.1 
Study Design  
8.2 
Setting   

13 
 
• 
History of connective tissue disease, history of malignancy (except for non-melanoma skin cancer) within the last 
5 years 
• 
Clinically significant active dermatologic disorders within the last 6 months 
• 
Use of oral retinoids, OTC or prescription antiwrinkle treatments, microdermabrasion, or chemical peels in the 
NLF area within the last 4 weeks or intention to use them during the study 
• 
Any prior cosmetic procedure or tissue augmentation at the NLF injection site within 1 year before study entry 
(or intent to undergo such a procedure during the study) 
• 
Pregnancy or breastfeeding 
 
Withdrawal Criteria 
• 
Withdrawal of consent by the participant 
• 
Noncompliance, including refusal of study medical requirements, refusal of procedures as stated in the study 
protocol, or use of prohibited medications 
• 
The occurrence of an undesirable event that causes the investigator to consider the participant's exclusion from 
the study 
• 
Not possible to follow the participant's condition (Loss to follow-up) 
• 
Change in participant’s conditions, which needs change of treatment due to investigator decision or administration 
of prohibited medications in the protocol 
 
 

14 
 
 
Study period 
 
Screening 
Intervention 
Time point 
Screening 
visit 
Visit 1 
Visit 2 
(Touch-up) * 
Visit 2’
** 
Visit 3 
Visit 4 
Time 
-7 to -1 days 
Day 1 
2 weeks ± 
3days 
4 weeks ± 
3days 
12 weeks ± 
3days 
24 weeks ± 
3days 
Informed consent 
× 
 
 
 
 
 
Eligibility Criteria 
× 
 
 
 
 
 
Randomization and 
allocation 
 
× 
 
 
 
 
Medical History 
× 
 
 
 
 
 
Face photography 
× 
× 
× 
× 
× 
× 
Intervention 
 
× 
× 
 
 
 
NLF severity score 
assessment 
× 
 
× 
× 
× 
× 
PGAIS assessment 
 
×*** 
× 
× 
× 
× 
Concomitant 
Medications 
× 
× 
× 
× 
× 
× 
Adverse Events 
reporting 
× 
× 
× 
× 
× 
× 
* Two treatments will be allowed over a 2-week period (initial treatment plus one touch-up) to achieve optimal 
correction of the NLFs. The level of correction will be assessed by the evaluating investigator at week 2 after the 
initial treatment and, if less than optimal, the treating investigator will be directed to retreat the under corrected NLF(s). 
** This visit is only conducted in patients with touch-up injection. 
 *** PGAIS in visit 1 is assessed after the intervention.  
8.3 
Study Timeline 

15 
 
The primary objective of this study is effectiveness assessment, including the mean level of improvement from 
baseline in NLF severity score by WSRS at week 24. The secondary outcomes of this study are to evaluate other 
effectiveness and safety parameters, including the number of subjects with improvement score in PGAIS at week 24 
compared to baseline, the proportion of NLFs maintaining a clinically significant improvement in NLF severity score 
(≥1-point reduction from baseline) at week 24, the volume required for optimal cosmetic result (initial treatment + 
touch-up), the number of NLFs receiving touch-up treatment, and the incidence of adverse events (injection site 
reactions) based on their severity.  
Variables in this study include patient demographic information (age, sex), history of filler injection, WSRS at each 
visit, patient’s medical history, patient’s medications, injection volume, receiving touch up treatment, PGAIS at each 
visit.  
The intensity of AEs will be graded according to the CTCAE v5.0, and terminology for AEs will be chosen according 
to the MedDRA system organ class and preferred term (MedDRA Desktop Browser 4.0 Beta). Seriousness will be 
also recorded for all AEs. 
All data will be collected by specialists and recorded in a booklet comprising five visits. The baseline information 
(demographics, past medical history, history of filler injection, patients’ medications), intervention information (e.g., 
dosage at visit1 and touch up), WSRS, and PGAIS will be recorded. All AEs will be reported based on the Medical 
Dictionary for Regulatory Activities (MedDRA) terms as the preferred term (PT) and system organ class (SOC) (14). 
All reported AEs will be graded according to the common terminology criteria for adverse events v5.0 (CTCAE v5.0) 
(15). Moreover, the seriousness of AEs will be specified using ICH-E2B guidelines (16). The causality relation will 
be assessed based on the World Health Organization (WHO) criteria (17).   
In an equivalence test of means using two one-sided tests on data from a paired design, a sample size of 97 achieved 
80% power at a 2.5% significance level. When the true difference between the means was 0.000, the standard deviation 
of the paired differences was 0.510, and the equivalence limits were -0.170 and 0.170. Considering a drop-out rate of 
10%, total sample size required is 108.  
8.7.1 
Main Summary Measures 
The descriptive analysis will be performed using frequency and percentage for categorical variables and mean and 
standard deviation for continuous variables. 
8.7.2 
Main Statistical Methods   
8.4 
Variables  
8.5 
Data Sources and Measurement
8.6 
Study Size 
8.7 
Statistical Methods 

16 
 
The mean level of improvement from baseline in NLFs severity score based on assessments by evaluating investigators 
and the injection volume to obtain optimal result will be analyzed using either a paired t-test or a signed-rank test. 
The number of patients with an improved score for the PGAIS, proportion of NLFs with clinically significant 
improvement and the number of NLFs receiving touch-up treatment will be analyzed using a McNemar test. 
The safety data will be analyzed primarily using summary statistics. Summary statistics are included the number of 
subjects (number and percentages) and then classified according to system organ class and preferred term for AEs and 
SAEs. The incidence of the preferred term for grades 3 and 4 of AEs will be reported. Moreover, causality will be 
assessed and its results will be reported by frequency and percentage. 
Espad Pharmed Co. conducts this study according to procedures that incorporate the ethical principles of GCP. The 
investigators participating in this study are among the most professional dermatologists in Iran.  
Before initiating the study, the PMS booklet will be checked and confirmed by the principal investigator regarding 
conformity with the study protocol. An instruction manual will be provided to train the personnel involved in filling 
the booklets. Participants’ recorded data in PMS booklets will be regularly monitored in terms of verification and 
validity. The recorded data in the booklets will be regularly exported and checked by a certified statistician for outlier 
determination to verify if data entry errors have occurred, and they will be rechecked if needed. 
The decision for a touch-up injection can be participant-driven rather than based on a real need to achieve optimal 
aesthetic results. 
9 
Protection of Human Subjects  
This study will be conducted in full conformance with the principles of the Declaration of Helsinki and GCP, along 
with local ethical approval requirements. Ethical approval is obtained from the local ethics committee of the affiliated 
university of the principal investigator. An informed consent form will be signed by the candidates who voluntarily 
accept to participate in the study. All personal data will be confidentially recorded and archived during the study and 
thereafter.  
10 Management and Reporting of Adverse Events/Adverse Reactions  
Adverse Event (AE) 
Any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical 
product and which does not necessarily have to have a causal relationship with this treatment. 
Adverse Drug Reaction (ADR) 
All noxious and unintended responses to a medicinal product related to any dose should be considered adverse drug 
reactions. 
8.8 
Quality Control  
8.9 
Limitations of the Research Methods  

17 
 
All AEs will be classified based on their severity and in accordance with the approved guidelines in the CTCAE v.5, 
published on November 27, 2017. According to these guidelines, Grade refers to the severity of the AE. 
Accordingly, Grades 1 to 5 with unique clinical descriptions of the severity of each AE are specified as follows: 
Grade 1 Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated. 
Grade 2 Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental 
Activities of Daily Living (ADL)1.  
Grade 3 Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of 
hospitalization indicated; disabling; limiting self-care ADL2.  
Grade 4 Life-threatening consequences; urgent intervention indicated. 
Grade 5 Death related to AE. 
 
The causality relation will be assessed based on the WHO criteria. To determine the relationship between an AE or 
ADR and the treatment used in the study, the following definitions are considered: 
Unrelated 
An adverse event for which no relationship can be inferred between it and the drug under consideration. 
Related 
Certain: Event or laboratory test abnormality, with plausible time relationship to drug intake • Cannot be explained 
by disease or other drugs • Response to withdrawal plausible (pharmacologically, pathologically) • Event definitive 
pharmacologically or phenomenologically (i.e., an objective and specific medical disorder or a recognised 
pharmacological phenomenon) • Rechallenge satisfactory, if necessary 
Probable / Likely: Event or laboratory test abnormality, with reasonable time relationship to drug intake • Unlikely 
to be attributed to disease or other drugs • Response to withdrawal clinically reasonable • Rechallenge not required 
Possible: Event or laboratory test abnormality, with reasonable time relationship to drug intake • Could also be 
explained by disease or other drugs • Information on drug withdrawal may be lacking or unclear 
Unlikely: Event or laboratory test abnormality, with a time to drug intake that makes a relationship improbable (but 
not impossible) • Disease or other drugs provide plausible explanations  
Conditional / Unclassified: Event or laboratory test abnormality • More data for proper assessment needed, or • 
Additional data under examination  
 
1 Instrumental ADL refer to preparing meals, shopping for groceries or clothes, using the telephone, managing money, 
etc. 
 
2  Self-care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, taking medications, and not 
bedridden. 
 

18 
 
Unassessable / Unclassifiable: Report suggesting an adverse reaction • Cannot be judged because information is 
insufficient or contradictory • Data cannot be supplemented or verified 
 
Recording Adverse Events 
All AEs that occur following drug administration will be meticulously documented in the patient's medical records. 
 
Seriousness of AEs will be assessed based on ICH-E2B guidelines 
seriousness criteria: 
− Results in death 
− Is life-threatening 
− Requires inpatient hospitalization or prolongation of existing hospitalization 
− Results in persistent or significant disability/incapacity (as per reporter's opinion) 
− Is a congenital anomaly/birth defect 
− Other medically important condition 
 
11 Plans for Disseminating and Communicating Study Results   
Study report will be prepared and submitted according to the ICH guidelines, and a journal article will be written 
to submit in peer-reviewed journals. 
12 References   
1. 
Voropai D, Dayan S, Botero LF, Botti C, Miller L, Pirayesh A. Aging of Skin, Soft Tissue, and Bone.  
Aesthetic Facial Anatomy Essentials for Injections: CRC Press; 2020. p. 13-6. 
2. 
Vashi NA, de Castro Maymone MB, Kundu RV. Aging Differences in Ethnic Skin. J Clin Aesthet Dermatol. 
2016;9(1):31-8. 
3. 
Grablowitz D, Sulovsky M, Höller S, Ivezic-Schoenfeld Z, Chang-Rodriguez S, Prinz M. Safety And 
Efficacy Of Princess(®) FILLER Lidocaine In The Correction Of Nasolabial Folds. Clin Cosmet Investig Dermatol. 
2019;12:857-64. 
4. 
He D, Workman CI, Kenett YN, He X, Chatterjee A. The effect of aging on facial attractiveness: An empirical 
and computational investigation. Acta Psychologica. 2021;219:103385. 
5. 
Waldman A, Maisel A, Weil A, Iyengar S, Sacotte K, Lazaroff JM, et al. Patients believe that cosmetic 
procedures affect their quality of life: an interview study of patient-reported motivations. Journal of the American 
Academy of Dermatology. 2019;80(6):1671-81. 
6. 
Fallacara A, Manfredini S, Durini E, Vertuani S. Hyaluronic acid fillers in soft tissue regeneration. Facial 
Plastic Surgery. 2017;33(01):087-96. 

19 
 
7. 
Stojanovič L, Majdič N. Effectiveness and safety of hyaluronic acid fillers used to enhance overall lip 
fullness: a systematic review of clinical studies. Journal of Cosmetic Dermatology. 2019;18(2):436-43. 
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13 Appendices 
Not applicable.