GLODERM 20L Evaluation Report 1.0 TITLE PAGE EVALUATION ... · Cross link Hyaluronic acid 20 mg/ml Title of Evaluation To assess the safety and performance of Dermal Fillers (GLODERM

GLODERM 20L Evaluation Report

Confidential Page 1 of 34

1.0 TITLE PAGE

EVALUATION

TITLE

: To assess the safety and performance of Dermal Fillers

(GLODERM 20L) in Patients with facial wrinkles (Glabellar Lines).

DEVICE : GLODERM 20L (Cross link Hyaluronic acid 20 mg/ml)

FILLING VOLUME 1 ml PFS

INDICATION : Correction of moderate to severe facial wrinkles and folds

EVALUATION

START DATE

: 16/07/2015

EVALUATION

COMPLETION

DATE

: 22/01/2016

PROTOCOL NO. : MOSS/GLO_20L/672015Version 1.0 date 06-07-2015

REPORT VERSION : 1.0, Date: 30/07/16

EVALUATION

PHASE

: Clinical Evaluation (PMCF)

Evaluation Centre:

Research Supported By:

Dr. Ivona Igerc

Furtinger DMD

Crnatkova 10

10 000 Zagreb

Croatia.

MOSS VISION INC. LTD.

120, Viglen House,

Alperton Lane,London- HA0 1HD

United Kingdom

Tel: +44 2086017128



2.0 SYNOPSIS

Research Supported By:

Moss Vision Inc. Ltd.

Individual Evaluation

table referring to part of

the dossier:

Volume:

Page:

For National Authority

Use Only

Name of Finished Product:

GLODERM 20L

Name of Active Ingredient:

Cross link Hyaluronic acid 20 mg/ml

Title of

Evaluation

To assess the safety and performance of Dermal Fillers (GLODERM 20L) in

Patients with facial wrinkles (Glabellar Lines).

Recruitment

period 3 months (12 weeks)

Evaluation

period

Total clinical evaluation duration was approximately 9 month including 3 month

of enrollment period and 6 month of follow up.

Clinical Phase

of Development Clinical Evaluation (PMCF)

Objectives To assess the safety and performance of GLODERM 20L in subjects with facial

wrinkle improvement and incidence of all adverse events at 6 months and any

systemic adverse event.

Methodology After the Screening the subjects who were eligible has been included in the

evaluation and have undergone the procedure by injecting GLODERM 20L to

face treated Area. All the assessment scale was done on Baseline and all clinical

Follow-up visits along with Photograph.

Clinical Follow-up:

Visit 1# 3 Months(±7 days) after the procedure

Visit 2# 6 Months(±7 days) after the procedure

Number of

subjects

(planned and

analyzed)

Total Patients Planned: 18

Total patients Enrolled: 18

Diagnosis and

main criteria

for inclusion

Inclusion Criteria:

Patients who met all of the below mentioned criteria were enrolled:

1. The patient must be ≥ 18 and ≤ 75 years of age.

2. The patient must be willing and able to provide consent including release

of copyright of facial images.

3. The patient must be willing to comply with the requirement of the



evaluation, including sequential photography or imaging for which

copyright will be held by the Sponsor.

4. The patient is willing and able to comply with the evaluation protocol.

5. The patient is seeking soft tissue augmentation treatment on the face.

6. The patient with folds, lines, wrinkles like Glabellar line. The patient has

a pre-treatment Wrinkle Severity Score (WSS) ≥ 2 for bilateral NLF to be

treated

7. The patient agrees to follow-up examinations out to 6 months post final

treatment.

Exclusion criteria:

Patients were excluded from the Evaluation if they had any of the following

criteria:

1. At risk in term of precautions, warnings and contra-indication referred in

the package insert of the evaluation devices,

2. Who underwent previous injection of permanent filler in the injected area.

3. Pregnant/lactating women

4. Subjects who have an allergy to lidocaine, prilocaine or other amide-type

anesthetic

5. Had a chemical peel at the NLF area within 4 weeks prior to evaluation

entry. In addition, subjects were restricted from undergoing chemical

peels at the NLF area for the duration of the evaluation.

6. Had any treatment with Botox® injections:

a. in the upper 1/3 of the face within 2 weeks prior to entry into the

evaluation, or

b. in the lower 2/3 of the face within 24 weeks prior to entry. In

addition, subjects were restricted from receiving Botox injections

in the face for the duration of the evaluation.

7. Had a history of hypo- or hyperpigmentation of the skin.

8. Tolerance to antibiotics or corticosteroids.

9. Had any infection, unhealed wound, or active inflammatory process (e.g.,

skin eruptions such as cysts, pimples, rashes, or hives) at the injection

site(s).

10. Immunocompromised/immunosuppressed (e.g., HIV-positive, transplant

recipient, or presently receiving chemotherapy).

11. A known history of keloids or bleeding disorders.



12. Leukoderma (vitiligo) or a family history of leukoderma or other

pigmentary disorders. Patient on Medication with blood thinners.

13. Patient on Medication with blood thinners like Aspirin, Clopidogril,

prasugril, ticlopidine,warfarin or antiaging medications like Vitamins

supplements

14. Severe physical, neurological or mental disease.

15. Excessive facial hair that might interfere with the evaluation of the

wrinkle assessments.

Investigational Products

Product

Formulation

(Generic Name)

Injectable Dermal Filler

(Cross link Hyaluronic acid 20 mg/ml)

Brand Name GLODERM 20L

Strength Cross link Hyaluronic acid 20 mg/ml

Dosage form Injection (Pre filled syringe)

Filled Volume 1 ml PFS

Manufacturer MOSS VISION INC. LTD.

Mode of

administration

Facial injection

Efficacy

Parameters

Primary efficacy parameter :

Change in GAIS Score from Day 0 to month 06

Secondary efficacy parameters:

Change in Glabellar severity score from Procedure day to 3 and 6 Months.

Safety

parameters Frequency and severity of Adverse events (Starting from the baseline visit

throughout to the follow-up visit)

Rationale for

sample size Not applicable. (Sample size calculation was not done for present study, as it was

pilot evaluation)

Statistical

analysis

Statistical analysis was done on Statistical Analysis System. The calculations

were based upon data captured in CRFs. The primary data set was analyzed on

the ITT population principle. All subjects enrolled were included in the analysis.

All safety calculations were performed on safety population (all population

enrolled). Efficacy evaluation was performed for qualifying subjects.

Considering the observational nature of this evaluation and the necessity to report

results on the targeted population, all endpoints were primarily analyzed on the

per-treatment evaluable population. In addition, for completeness the ITT



analysis was performed.

Detailed descriptive analyses of the evaluation endpoints were performed after

each follow-up time point. The LOCF method was used to impute the missing

values. All calculations were based on available data with missing data excluded.

Any unused or spurious data was noted as appropriate in the final report. The

dropout rate was expected to be less than 10%.

Summary of Results:

Efficacy

Results

All patients involved in the study were Caucasian. Mean Patient age was

60.13±11.65 years for patients included in present study and range was 42-81

Years. Patients with Type II Fitzpatrick skin prototype (55.6%) were higher than

other type.

Global Aesthetic Improvement scale score was considered as primary efficacy

parameter to measure the subject’s satisfaction with the wrinkle improvement.

Study results revealed that significant improvement was observed at 03 month

follow up and remain consistent up to 06 month follow up for all patients. Mean

Global Aesthetic Improvement scale Score was improved to 2.4 ± 0.51 at 3

months follow up which was -2.0 ± 0.69 at baseline and persisted same value at 6

months follow up. While evaluation of statistical significance by Wilcoxon

Signed Ranks Test, p (<0.001) value indicated highly significant improvement in

mean GAIS Score. results shown that 10 patients had much improved (55.6%)

and 8 patients had very much improved (44.4%) which persisted at 6 month

follow up. Improvement in patient condition is clinically significant because 4

patients have worse condition of disease, 10 patients had much worse condition

and 4 patients had very much worse condition before study treatment.

As secondary efficacy evaluation, changes in Glabellar severity score from Day 0

(Procedure Day) and change in from Procedure day to 3 and 6 Months were

assessed in present study. Glabellar severity score was improved at 03 month

follow up and remain consistent up to 06 month follow up for majority (77.7%)

of patients.

Mean Glabellar severity score was reduced to 1.61 ± 0.61 at 3 months follow up

which was 2.17 ± 0.79 at baseline and persisted same value at 6 months follow

up. While evaluation of statistical significance by Wilcoxon Signed Ranks Test, p

(p=0.002) value indicated highly significant reduction in mean Glabellar severity

score. Statistical significance in Mean Glabellar severity score reduction was

supportive to clinical improvement in wrinkles, as assessed by study Investigator

in majority of patients and patient satisfaction after treatment.

Number of patients with moderately deep wrinkles had reduced at 3 and 6 months

follow up (5.6%) compared to baseline (38.9%). However, none of patients with

“No Wrinkles” at follow up evaluation indicated that “Moderate Deep wrinkles”



have been improved to “Just perceptible Wrinkles” in those patients.

Safety Results None of the patients reported adverse events in present study. All patients

reported expected feel while Injection and none of patients have complication due

to device failure, indicated excellent Device Palatability in present study.

Conclusion In present evaluation, single dose administration of GLODERM 20L is found

effective in treatment of facial wrinkles (Glabellar lines) and safe with good

device palatability till 6 months follow up.



3.0 TABLE OF CONTENTS 1.0 TITLE PAGE ...................................................................................................................................... 1 1.1 STATEMENT OF INVESTIGATOR FOR GOOD CLINICAL PRACTICE COMPLIANCE ................................... 2 2.0 SYNOPSIS........................................................................................................................................... 3 3.0 TABLE OF CONTENTS .................................................................................................................... 8 4.0 LIST OF ABBREVIATIONS ............................................................................................................ 10 5.0 ETHICS ............................................................................................................................................. 11 5.1 INDEPENDENT ETHICS COMMITTEE (IEC) ............................................................................. 11 NOT APPLICABLE ......................................................................................................................................... 11 5.2 ETHICAL CONDUCT OF THE EVALUATION ................................................................................. 11 NOT APPLICABLE ......................................................................................................................................... 11 5.3 SUBJECT INFORMATION AND CONSENT ..................................................................................... 11 NOT APPLICABLE ......................................................................................................................................... 11 6.0 INVESTIGATORS AND EVALUATION ADMINISTRATIVE STRUCTURE ............................ 11 7.0 INTRODUCTION ............................................................................................................................. 12 8.0 EVALUATION OBJECTIVE(S) ...................................................................................................... 14 9.0 INVESTIGATION PLAN ................................................................................................................. 14 9.1 OVERALL EVALUATION DESIGN AND PLAN-DESCRIPTION ............................................... 14 9.2 DISCUSSION OF EVALUATION DESIGN, INCLUDING THE CHOICE OF CONTROL

GROUPS ........................................................................................................................................... 16 9.3 SELECTION OF EVALUATION POPULATION ........................................................................... 16 9.3.1 Inclusion Criteria ................................................................................................................................ 16 9.3.2 Exclusion Criteria ............................................................................................................................... 16 9.3.3 Removal of Subjects from Therapy or Assessment ............................................................................... 17 9.4 TREATMENTS ................................................................................................................................. 17 9.4.1 Treatments Administered .................................................................................................................... 17 9.4.2 Identity of Investigational Device(s) ........................................................................................................... 18 9.4.3 Methods of Assigning Subjects to Treatment Groups ........................................................................... 18 9.4.5 Blinding .............................................................................. 18 9.4.6 Prior and Concomitant Therapy ........................................................................................................... 18 9.5 EFFICACY AND SAFETY VARIABLES ........................................................................................ 18 9.5.1 Efficacy and Safety Measurements Assessed and Flow Chart ............................................................... 18 9.5.2 Appropriateness of Measurements ....................................................................................................... 19 9.5.3 Primary Efficacy Variable(s) ............................................................................................................... 19 9.5.4 Device Concentration Measurements ................................................................................................... 19 9.5.5 Sample Collection & Processing .......................................................................................................... 19 9.6 DATA QUALITY ASSURANCE ...................................................................................................... 19 9.7 STATISTICAL METHODS PLANNED IN THE PROTOCOL AND DETERMINATION

OF SAMPLE SIZE ........................................................................................................................... 20 9.7.1 Statistical and Analytical Plans ................................................................................................................... 20 9.7.2 Determination of Sample Size .................................................................................................................... 20 9.8 CHANGES IN THE CONDUCT OF THE EVALUATION OR PLANNED ANALYSES ............... 20 10 EVALUATION SUBJECTS ............................................................................................................. 20 10.1 DISPOSITION OF SUBJECTS................................................................................................................ 20 10.2 PROTOCOL DEVIATION(S) .................................................................................................................. 21 11 EFFICACY EVALUATION ............................................................................................................. 21 11.1 DATA SETS ANALYSED ......................................................................................................................... 21 11.2 DEMOGRAPHIC CHARACTERISTICS ........................................................................................ 21



11.3 EFFICACY RESULTS AND TABULATIONS OF INDIVIDUAL SUBJECT DATA ..................... 22 11.3.1 Analysis of Efficacy ................................................................................................................................. 22 11.3.2 Statistical/Analytical Issue ................................................................................................................... 28 11.3.3 Device Dose, Device Concentration, and Relationships to Response ......................................................... 29 11.3.4 Interactions ......................................................................................................................................... 29 11.3.5 Efficacy Conclusions ........................................................................................................................... 29 12 SAFETY EVALUATION .................................................................................................................. 29 12.1 EXTENT OF EXPOSURE ................................................................................................................ 29 12.2 ADVERSE EVENTS (AES) ............................................................................................................... 29 12.3 DEATHS, OTHER SERIOUS ADVERSE EVENTS, AND OTHER SIGNIFICANT ADVERSE

EVENTS 31 12.4 CLINICAL LABORATORY EVALUATION .................................................................................. 31 12.4.1Listing of Individual Laboratory Measurements by Subject and Each Abnormal Laboratory Value ......... 31 12.4.2 Evaluation of Each Laboratory Parameter ................................................................................................. 31 12.5 SAFETY CONCLUSIONS ................................................................................................................ 32



4.0 LIST OF ABBREVIATIONS

ADE Adverse Device Effect

AE Adverse Event

AIDS Acquired Immune Deficiency Syndrome

CRF Case Report Form

CRO Contract (Clinical) Research Organization

GAIS Global Aesthetic Improvement scale

FU Follow Up

GCP Good Clinical Practice

ICH International Conference on Harmonization

IFU Instructions For Use

IP Investigational Product

ISO International Standardization Organization

ITT Intent To Treat

LOCF Last Observation Carried Forward

MFWS Modified Fitzpatrick Wrinkle Scale

N/A Not Applicable

SAE Serious Adverse Event

SADE Serious Adverse Device Effect

SAS Statistical Analysis System

UADE Unanticipated Adverse Device Effects



5.0 ETHICS

5.1 INDEPENDENT ETHICS COMMITTEE (IEC)

Not applicable

5.2 ETHICAL CONDUCT OF THE EVALUATION

Not applicable

5.3 SUBJECT INFORMATION AND CONSENT

Not applicable

6.0 INVESTIGATORS AND EVALUATION ADMINISTRATIVE STRUCTURE

Present Evaluation was conducted at Furtinger DMD, Crnatkova 10, 10 000 Zagreb, Croatia.

The details of investigator and Evaluation administrative structure are given below in table 1.

Table 1: Evaluation administrative structure

Principal Investigator : Dr. Ivona Igerc

Evaluation Center : Furtinger DMD

Crnatkova 10

10 000 Zagreb

Croatia

Evaluation supported by : Moss Vision Inc. Ltd.

Medical Writing and

Statistical Services

: Ethitrials Contract Research Pvt. Ltd.

Ahmedabad



7.0 INTRODUCTION

The popularity of dermal fillers has grown rapidly in recent years because they offer the

rejuvenative and enhancing aesthetic improvements previously only achievable with surgery,

but at lower cost and with limited-to-no recovery time. According to data from the American

Society for Aesthetic Plastic Surgery (ASAPS), more than 1.6 million dermal filler treatments

were performed in 2011, making them the second most popular nonsurgical cosmetic

procedure performed in the USA after neuromodulators; the latter procedure is frequently

performed in concert with dermal filler injections.1

As public awareness and acceptance of dermal fillers grows, so does the size of the market,

with an estimated 160 products currently available worldwide from more than 50 companies.

Their main indications are the filling of rhytides and folds, and correction of soft tissue loss

due to disease or age.2 Increasingly, fillers are used for volume replacement and enhancement

procedures,3 including cheek and chin augmentation, tear trough correction, nose reshaping,

midfacial volumization, lip enhancement, hand rejuvenation, and the correction of facial

asymmetry. As the indications and the number of procedures performed increase, the number

of complications will likely also increase.

Understanding the different characteristics, capabilities, injection techniques, risks, and

limitations of available fillers is essential for injectors to reduce the risk of complications,

improve patient outcomes, and care for patients who have experienced adverse events. This

requires expert familiarity with the properties and potential complications of a wide range of

products, including those that are not available in the injector’s country of practice, as patients

may present with adverse reactions to fillers that were injected abroad. Particularly important

is how the incidence of local adverse events following treatment is related to the injection

technique versus the chemical composition of the dermal filler.4

Several methods of categorizing dermal fillers exist, but for a discussion of dermal filler

complications it is perhaps most useful to categorize in terms of biodegradable (moderate and

long duration) versus non-biodegradable fillers, and in terms of particulate versus non-

particulate fillers. Moderate duration biodegradable fillers, such as collagen and the hyaluronic

acid (HA) fillers, are reabsorbed by the body quite quickly, so their cosmetic effects are

relatively short-lived. HA derivatives are the most widely used biodegradable fillers in both

Europe and the USA,1,5

and generally have effects lasting 6–18 months depending on the

source and extent of cross-linking and concentration and particle size of each product.6 HAs

are linear polymeric dimers of N-acetyl glucosamine and glucuronic acid, which differ in the

proprietary methods used to cross-link their dimers, their degree and method of chain cross-

linking, the uniformity and size of their particles, and their concentration. These characteristics

all have a significant impact on the clinical effect of these products. Increased cross-linking



and concentration increase the viscosity and elasticity as well as the resistance to degradation

by native hyaluronidase. The hydrophilic nature of HA means that the more concentrated

and/or large particle products will tend to absorb more water, and thus produce more tissue

swelling after injection. HA products are also characterized by the size of their microspheres.

Biphasic fillers, such as Restylane, Perlane and Macrolane (all Q-MED, Uppsala, Sweden),

contain a range of microsphere sizes. Monophasic HA products, such as Juvederm (Allergan,

Irvine, CA, USA), Belotero (Merz Pharmaceuticals GmbH, Frankfurt, Germany), Teosyal

(Clarion Medical Technologies, Cambridge, ON, Canada), Prevelle Silk (Mentor Worldwide

LLC, Santa Barbara, CA, USA), and Varioderm™ (Adoderm, Langenfeld, Germany), contain

homogeneous microspheres and are the preferred HA of most other companies. The different

HAs had varying degrees of hardness (G’), which will influence their suitability for a

particular procedure. In general, the greater the G’ of the product, the deeper it should be

injected. It should be noted that while more concentrated products with a greater degree of

cross-linking have a longer duration of effect, they also increase reactivity in the body and thus

the risk of inflammation and granuloma formation.

GLODERM 20L is dermal filler made from a highly purified form of Hyaluronic Acid from

non-animal origin that mimics the effects of natural Hyaluronic Acid. When injected just

below the surface of the Skin, GLODERM 20L adds volume to the Skin, smoothing unwanted

lines and wrinkles. GLODERM 20L consists of cross-linked Hyaluronic Acid formulated to a

concentration of 30 mg / ml suspended in a physiological buffer. GLODERM 20L dermal

fillers are used for filling any deep depression of the skin via deep dermis injection as well as

for lip enhancement and Cheekbone augmentation. The rheological properties of GLODERM

20L provide excellent cosmetic results and enable the intradermal anatomical space to be

rapidly reconstituted.

GLODERM 20L dermal filler is a nonsurgical, physician-administered treatment for

correction of facial wrinkles. Using a fine needle, your healthcare professional eases

GLODERM 20L under the Skin to fill the soft tissue of the dermis. This adds volume and

diminishes the appearance of wrinkles and provide excellent look instantly. Since GLODERM

20L contains only Hyaluronic Acid, a natural constituent of human tissues, it is biocompatible

and very safe. These products are eventually broken down naturally .There are no

contraindications to the use of these products and the precautions are mainly those that should

be observed for any intradermal injection. Unlike rooster-derived Hyaluronic Acids and bovine

collagen products, GLODERM 20L is free from animal proteins and latex free. This limits any

risk of animal based disease transmissions or development of allergic reactions to animal

proteins.7



At present, various hyaluronic acids are being used to rejuvenate facial skin. Comparative

study of single cross-linked hyaluronic acid (SCHA) versus double cross-linked hyaluronic

acid (DCHA) was conducted by Kono T et al. Objective was to compare the effectiveness and

complications of SCHA versus DCHA in the treatment of glabellar lines. Ten female patients

were enrolled in this randomized, evaluator-blind study. One side (left vs. right) of each

patient's glabellar lines was treated with SCHA and the other side was treated with DCHA.

Two independent blinded observers reviewed the clinical photographs at 3, 6, 9, and 12

months after the treatment and assessed for degree of improvement as well as complications.

The two products were equally effective in producing an optimal cosmetic result, although at

6, 9, and 12 months posttreatment, a higher proportion of patients showed over 50%

improvement with DCHA than with SCHA. At 12 months posttreatment, DCHA was

considered superior in 70% of patients, whereas SCHA was superior in 10% of patients. Both

SCHA and DCHA are equally effective in producing an optimal cosmetic result. DCHA

provides a more durable esthetic improvement when compared to SCHA in the treatment of

glabellar lines.7

The present document is a clinical Evaluation report of Evaluation conducted to evaluate effect

and safety of GLODERM 20L.

8.0 EVALUATION OBJECTIVE(S)

To assess the safety and performance of GLODERM 20L in subjects with facial wrinkle

improvement and incidence of all adverse events at 6 months and any systemic adverse event.

9.0 INVESTIGATION PLAN

9.1 OVERALL EVALUATION DESIGN AND PLAN-DESCRIPTION

Present Evaluation was single centric, non-randomized, open label clinical evaluation in

patients with facial wrinkles.

A total of 18 patients who fulfilled inclusion/exclusion criteria were enrolled in present

Evaluation.

The appropriate quantity of device was injected or implanted at treatment site as outlined.

GLODERM 20L is mainly designed to be injected into the mid dermis. The device was used

by physicians who have undertaken specific training in injection techniques for such fillings

and efficacy data were collected during the follow-up visits at 3 and 6 months. Safety was

evaluated during treatment as well as follow-up visits conducted after 3 and 6 months of

treatment.



A total of 3 visits were conducted during the evaluation. First visit is baseline visit, evaluation

device administration was done and thereafter there were two follow-up visits. The follow-up

visits were performed at 3 and 6 months after the completion of device administration.

Patients were screened as per the Inclusion/exclusion criteria before enrolment in present

evaluation. Investigator had explained about the evaluation in detail to the patients. The

Evaluation procedures are detailed in below table 2.

Table 2: Evaluation Schedule

Event Screening/

Baseline Procedure

Post –

procedure

Day 0

FU 1

3

Months

FU 2

6

Months

Type of contact

Hospital

visit Hospital

visit

Inclusion/

exclusion Criteria X

Physical examination X

Medical History X

Photograph X X X X

GAIS Assessment X X X X

Glabellar Line

Assessment X X X X

Adverse Events and

Serious Adverse

Event Monitoring X X X X

Following data were planned to collect in present evaluation:

Demographic information: The available information about Gender, Race/Ethnicity and

Fitzpatrick skin phototype were captured.

History of smoking / drinking habits

Medical history: The details of past medical history were documented.

Pain management method: The data about the use pain management method was collected.



Treated Area Details: The details about treated area, injection volume, injection deepness etc.

was collected

Face examination assessment: The details like Physical Examination of Face, Full Face Global

Aesthetic Improvement, Change in Glabellar severity score were collected.

9.2 DISCUSSION OF EVALUATION DESIGN, INCLUDING THE CHOICE OF

CONTROL GROUPS

Not applicable.

9.3 SELECTION OF EVALUATION POPULATION

Subjects recruited to the Evaluation were taken from the standard population confirmed for

following inclusion and exclusion criteria.

9.3.1 Inclusion Criteria

Subjects who fulfilled the below criteria were considered for inclusion into this Evaluation.

1. The patient must be ≥ 18 and ≤ 75 years of age.

2. The patient must be willing and able to provide consent including release of copyright

of facial images.

3. The patient must be willing to comply with the requirement of the evaluation, including

sequential photography or imaging for which copyright will be held by the Sponsor.

4. The patient is willing and able to comply with the evaluation protocol.

5. The patient is seeking soft tissue augmentation treatment on the face.

6. The patient with folds, lines, wrinkles like Glabellar line.

7. The patient has a pre-treatment Wrinkle Severity Score (WSS) ≥ 2 for bilateral NLF to

be treated

8. The patient agrees to follow-up examinations out to 6 months post final treatment.

9.3.2 Exclusion Criteria

The subjects were excluded based on the following criteria:

1. At risk in term of precautions, warnings and contra-indication referred in the package

insert of the evaluation devices,

2. Who underwent previous injection of permanent filler in the injected area.

3. Pregnant/lactating women



4. Subjects who have an allergy to lidocaine, prilocaine or other amide-type anesthetic

5. Had a chemical peel at the NLF area within 4 weeks prior to evaluation entry. In

addition, subjects were restricted from undergoing chemical peels at the NLF area for

the duration of the evaluation.

6. Had any treatment with Botox® injections:

a. in the upper 1/3 of the face within 2 weeks prior to entry into the evaluation, or

b. in the lower 2/3 of the face within 24 weeks prior to entry. In addition, subjects

were restricted from receiving Botox injections in the face for the duration of

the evaluation.

7. Had a history of hypo- or hyperpigmentation of the skin.

8. Tolerance to antibiotics or corticosteroids.

9. Had any infection, unhealed wound, or active inflammatory process (e.g., skin

eruptions such as cysts, pimples, rashes, or hives) at the injection site(s).

10. Immunocompromised/immunosuppressed (e.g., HIV-positive, transplant recipient, or

presently receiving chemotherapy).

11. A known history of keloids or bleeding disorders.

12. Leukoderma (vitiligo) or a family history of leukoderma or other pigmentary disorders.

Patient on Medication with blood thinners.

13. Patient on Medication with blood thinners like Aspirin, Clopidogril, prasugril,

ticlopidine,warfarin or antiaging medications like Vitamins supplements

14. Severe physical, neurological or mental disease.

15. Excessive facial hair that might interfere with the evaluation of the wrinkle

assessments.

9.3.3 Removal of Subjects from Therapy or Assessment

Not applicable. All patients had completed evaluation and were included for safety and

efficacy assessment.

9.4 TREATMENTS

9.4.1 Treatments Administered

Patients were administered with a injection of GLODERM 20L at treatment site as outlined.

Bring the GLODERM 20L 20 mg/ml Syringe at room temperature at least 30 min prior to use

mean while treatment site must be kept clean with appropriate disinfectant. Open the tip cap of

GLODERM 20L Syringe and the needle attached firmly with luer lock of PFS. Check the

injectability of the syringe by pressing plunger rod slightly. Allow some solution to come out

of the needle to confirm the clarity. GLODERM 20L is mainly designed to be injected into the

mid dermis. Total of 18 patients received injection and were included in the efficacy analysis.



9.4.2 Identity of Investigational Device(s)

Table 3 : Summary of Investigational Device

Product Evaluation test product

Formulation

(Generic Name)

Injectable Dermal Filler

(Cross link Hyaluronic acid 20 mg/ml)

Brand Name GLODERM 20L

Strength Cross link Hyaluronic acid 20 mg/ml

Dosage form Injection (Pre filled syringe)

9.4.2.1 Investigational Product (IP) Receipt, Dispensing and Handling

Not applicable

9.4.3 Methods of Assigning Subjects to Treatment Groups

Present Evaluation is single arm evaluation with only one treatment. A method of Assigning

Subjects to Treatment Groups is not applicable.

9.4.4 Selection of Doses in the Evaluation

GLODERM 20L is available in single used glass syringe prefilled with 1ml sterile cross linked

hyaluronic acid gel includes 2 single use 27 g1/2

sterile needles set (Containing cross link

Hyaluronic acid: 20 mg/ml)

9.4.5 Blinding

Not applicable, as present Evaluation is single arm open label Evaluation.

9.4.6 Prior and Concomitant Therapy

As per the protocol there was no any mandatory prior or concomitant therapy required during

the Evaluation.

9.5 EFFICACY AND SAFETY VARIABLES

9.5.1 Efficacy and Safety Measurements Assessed and Flow Chart

Efficacy measurements

In this evaluation changes in Global Aesthetic Improvement scale from Day 0 to 3 and 6

Months were used to assess the efficacy of GLODERM 20L (cross link Hyaluronic acid: 20

mg/ml).



Safety measurements

Safety was measured by evaluation of treatment emergent adverse events and Serious Adverse

Event (SAE).

Adverse Event (AE)

Any untoward medical occurrence in a patient or clinical investigation subject administered a

pharmaceutical product and which does not necessarily have a causal relationship with this

treatment. An adverse event (AE) can therefore be any unfavorable and unintended sign

(including an abnormal laboratory finding), symptom, or disease temporally associated with

the use of a medicinal (investigational) product, whether or not related to the medicinal

(investigational) product.

Serious Adverse Event (SAE)

Any untoward medical occurrence that at any dose:

- results in death,

- is life-threatening,

- requires inpatient hospitalization or prolongation of existing hospitalization,

- results in persistent or significant disability/incapacity,

or

- is a congenital anomaly/birth defect

9.5.2 Appropriateness of Measurements

Not applicable

9.5.3 Primary Efficacy Variable(s)

Change in GAIS Score from Day 0 to month 06

9.5.4 Device Concentration Measurements

Not applicable

9.5.5 Sample Collection & Processing

Not applicable

9.6 DATA QUALITY ASSURANCE

Not applicable



9.7 STATISTICAL METHODS PLANNED IN THE PROTOCOL AND

DETERMINATION OF SAMPLE SIZE

9.7.1 Statistical and Analytical Plans

Statistical analysis was done on Statistical Analysis System. The calculations were based upon

data captured in CRFs. The primary data set was analyzed on the ITT population principle. All

subjects enrolled were included in the analysis. All safety calculations were performed on

safety population (all population enrolled). Efficacy evaluation was performed for qualifying

subjects.

Considering the observational nature of this evaluation and the necessity to report results on

the targeted population, all endpoints were primarily analyzed on the per-treatment evaluable

population. In addition, for completeness the ITT analysis was performed.

Detailed descriptive analyses of the evaluation endpoints were performed after each follow-up

time point. The LOCF method was used to impute the missing values. All calculations were

based on available data with missing data excluded. Any unused or spurious data was noted as

appropriate in the final report. The dropout rate was expected to be less than 10%.

9.7.2 Determination of Sample Size

Not applicable. (Sample size calculation was not done for present study, as it was pilot

evaluation)

9.8 CHANGES IN THE CONDUCT OF THE EVALUATION OR PLANNED ANALYSES

There were no changes in the conduct of the Evaluation or planned analysis.

10 EVALUATION SUBJECTS

10.1 DISPOSITION OF SUBJECTS

A total of 18 patients with facial wrinkle of either gender with age ≥ 18 years and ≤ 75 years

were enrolled in this Evaluation.

Patients Enrolled

N=18

Patients for

Efficacy Evaluation

N=18

Patients for Safety

Evaluation N=18



10.2 PROTOCOL DEVIATION(S)

There was no protocol deviations reported during conduct of evaluation.

11 EFFICACY EVALUATION

11.1 DATA SETS ANALYSED

Table 4 Data Set Analyzed

All Enrolled

(N=18)

Efficacy Population 18 (100%)

Safety Population 18 (100%)

Eighteen (18) patients with facial wrinkles were enrolled in the Evaluation. All of eighteen

patients completed evaluation treatment and evaluation follow up (3 and 6 months) as per

protocol and were included in efficacy analysis.

All of Eighteen (18) patients were included for safety evaluation.

11.2 DEMOGRAPHIC CHARACTERISTICS

Demographic variables included Age, Gender, Race/Ethnicity and Fitzpatrick skin phototype.

Only female patients (100%) were enrolled in evaluation. Mean Patient age was 60.13±11.65

years for patients included in present study and range was 42-81 Years. All patients involved

in the study were Caucasian. None of patients have drinking habit or significant medical

history at baseline, except one patient have smoking history.

Patients have different Fitzpatrick skin phototype given in table below:

Table 5: Fitzpatrick skin phototype

Frequency Percent

Valid I 4 22.22%

II 10 55.56%

III 3 16.67%

IV 1 5.56%

Total 18 100.00



Patients with Type II Fitzpatrick skin phototype (55.6%) were higher than others and it is

represented in below graph (Figure 1)

Figure 1: Percentage of patients with Fitzpatrick skin phototype

11.3 EFFICACY RESULTS AND TABULATIONS OF INDIVIDUAL SUBJECT DATA

11.3.1 Analysis of Efficacy

Pain Management method and Treatment:

All patients were injected Injection volume of 0.4 ml as per pain management method and

Individual patient clinical need.

All patients reported expected feel while Injection and none of patients have complication due

to device failure, indicated excellent Device Palatability in present study.

PRIMARY EFFICACY:

Global Aesthetic Improvement scale

In this evaluation, changes in Global Aesthetic Improvement scale (GAIS) Score from Day 0

(Procedure Day) to 3 and 6 Months were assessed to evaluate efficacy of GLODERM 20L.

Following grading scale for GAIS was used in study:

GAIS Score:

3 = Very Much Improved

2 = Much Improved



1= Improved

0 = No Change

-1 = Worse

-2 = Much Worse

-3 = Very Much Worse

Changes in GAIS score from Day 0 to month 03 and 06 were represented in figure below.

(Figure 2) From the graph, we can conclude that significant improvement was observed at 03

month follow up and remain consistent up to 06 month follow up for all patients.

Figure 2: Changes in GAIS score from baseline to month 03 and month 06

The mean value of GAIS score at baseline, 3 and 6 months follow up was given in table below

and also represented in graph. (Table 7 and figure 3)

Table 7: GAIS score (mean value)

GAIS score (Mean ±S.D.)

Baseline -2.0 ± 0.69

3 month follow up 2.4 ± 0.51




Figure 3: Change in GAIS score (mean value) from baseline to month 03 and month 06

-2.00

2.44 2.44

-3.00

-2.00

-1.00

0.00

1.00

2.00

3.00

At Baseline at 3 Months at 6 Months

Me

an G

AIS

Sco

reAt Baseline

at 3 Months

at 6 Months

Mean Global Aesthetic Improvement scale Score (GAIS) was -2.0 ± 0.69 at baseline. GAIS

had improved significantly with mean GAIS score of 2.4 ± 0.51 (Mean improvement of 4.4) at

3 months follow up. Same mean value of GAIS score (2.4 ± 0.51) was also observed at 6

months follow up. While evaluation of statistical significance by Wilcoxon Signed Ranks Test,

p (<0.001) value indicated highly significant improvement in mean GAIS Score (at 3 and 6

months follow up).

Table 8: Comparison of GAIS Score

GAIS GAIS

Grade

Baseline

N (%)

At 3 Months

Follow up

N (%)

At 6 Months

Follow Up

N (%)

Very Much

Improved 3 0 8 (44.4%) 8 (44.4%)

Much Improved 2 0 10 (55.6%) 10 (55.6%)

Improved 1 0 0 0

No Change 0 0 0 0

Worse -1 4 (22.2%) 0 0

Much Worse -2 10 (55.6%) 0 0

Very Much

Worse -3 4 (22.2%) 0 0

From results represented in above table, results shown that 10 patients had much improved

(55.6%) and 8 patients had very much improved (44.4%) which persisted at 6 month follow

up. Improvement in patient condition is clinically significant because 4 patients have worse



condition of disease, 10 patients had much worse condition and 4 patients had very much

worse condition before study treatment.



SECONDARY EFFICACY PARAMETER:

Glabellar severity score assessment:

In this evaluation, changes in Glabellar severity score from Day 0 (Procedure Day) and change

in from Procedure day to 3 and 6 Months were assessed as secondary efficacy endpoint of

GLODERM 20L.

Following grading scale for Glabellar severity score was used in study:

Glabellar severity score Scale:

0 No wrinkles

1 Just perceptible Wrinkles

2 Shallow Wrinkles

3 Moderate Deep wrinkles

4 Deep Wrinkles

5 Very Deep Wrinkles

Changes in Glabellar severity score from Day 0 to month 03 and 06 were represented in figure

below. (Figure 4) From the graph, we can conclude that significant improvement was observed

at 03 month follow up and remain consistent up to 06 month follow up for majority of patients.

Glabellar severity score remain unchanged for 4 out of 18 patients.

Figure 4: Changes in Glabellar severity score from baseline to month 03 and month 06

22.20%

44.40% 44.40%38.90%

50% 50%

38.90%

5.60% 5.60%

0

0.1

0.2

0.3

0.4

0.5

0.6

Baseline At 3 Months Follow up At 6 Months Follow Up

Just perceptible Wrinkles

Shallow Wrinkles

Moderate Deep wrinkles



The mean value of Glabellar severity score at baseline, 3 and 6 months follow up was given in

table below and also represented in graph. (Table 9 and figure 5)

Table 9: Glabellar severity score (mean value)

Glabellar severity score

(Mean ±S.D.)

Baseline 2.17 ± 0.79



Figure 5: Change in Mean Glabellar severity score from baseline to 3 and 6 month follow

up

2.17

1.61 1.61

0.00

1.00

2.00

3.00

Baseline 3 Months 6 Months

Me

an G

lab

ella

r Li

ne

Sco

re

Baseline

3 Months

6 Months

Mean Glabellar severity score was 2.17 ± 0.79 at baseline. Glabellar severity score had

reduced significantly with mean score of 1.61 ± 0.61 at 3 months follow up. Same mean value

of GAIS score (1.61 ± 0.61) was also observed at 6 months follow up.While evaluation of

statistical significance by Wilcoxon Signed Ranks Test, p (p=0.002) value indicated highly

significant reduction in mean Glabellar severity score. Statistical significance in Mean

Glabellar severity score reduction was supportive to clinical improvement in wrinkles, as

assessed by study Investigator in majority of patients and patient satisfaction after treatment.



Table 10: Comparison of Glabellar severity score

Glabellar severity

score

Glabellar

severity

score

grade

Baseline

N (%)

At 3 Months

Follow up

N (%)

At 6 Months

Follow Up

N (%)

No wrinkles 0 0 0 0

Just perceptible

Wrinkles 1 4 (22.2%) 8 (44.4%) 8 (44.4%)

Shallow Wrinkles 2 7 (38.9%) 9 (50%) 9 (50%)

Moderate Deep

wrinkles 3 7 (38.9%) 1 (5.6%) 1 (5.6%)

Deep Wrinkles 4 0 0 0

Very Deep

Wrinkles 5 0 0 0

Comparison of percentage of patients with different grade for Glabellar severity have shown

that only one (5.6%) patient have moderate deep wrinkles while 3 and 6 month evaluation,

against 7 (38.9%) patients having moderate deep wrinkles at baseline. However, none of

patients with “No Wrinkles” at follow up evaluation indicated that “Moderate Deep wrinkles”

have been improved to “Just perceptible Wrinkles” in those patients.

11.3.2 Statistical/Analytical Issue

Not Applicable.

11.3.2.1 Adjustments for Covariates

Not Applicable.

11.3.2.2 Handling of Dropouts or Missing Data

There was no dropout or missing data in the evaluation.

11.3.2.3 Interim Analyses and Data Monitoring

Not applicable.

11.3.2.4 Multicentre Studies

Not applicable.



11.3.2.5 Multiple Comparison/Multiplicity

Not applicable.

11.3.2.6 Use of an “Efficacy Subset” of Subjects

Not applicable.

11.3.2.7 Active-Control Studies Intended to Show Equivalence

Not applicable.

11.3.2.8 Examination of Subgroups

Not applicable.

11.3.3 Device Dose, Device Concentration, and Relationships to Response

Not Applicable. All the patients evaluable for efficacy received same dose of Evaluation

treatment.

11.3.4 Interactions

Not Applicable

11.3.5 Efficacy Conclusions

In present evaluation, injection of GLODERM 20L is found effective in treatment of facial

wrinkles.

12 SAFETY EVALUATION

12.1 EXTENT OF EXPOSURE

All 18 patients received injection of Evaluation treatment.

12.2 ADVERSE EVENTS (AEs)

None of patients reported adverse events in present study. All patients reported expected feel

while Injection and none of patients have complication due to device failure, indicated

excellent Device Palatability in present study.



Table 11: Treatment Emergent AE

Safety Population (N= 18)

n % E

Any event 0 0(0.0%) 0

Table 12 : Evaluation of Treatment Emergent Adverse Events (TEAE)

Safety Population

(N= 18)

Total no. of subjects who had Adverse event, n (%)*

Yes 0(0%)

No 0(0.0%)

Total no .of Adverse reaction, n 0

Total no. of subjects having Serious Adverse event, n (%)* 0

Yes 0(0.0%)

No 0(0.0%)

Total no .of Serious Adverse event, n 0

Ongoing status of Adverse event, n (%)**

Yes 0(0.0%)

No 0(0.0%)

Severity, n (%) **

Mild 0(0.0%)

Moderate 0(0.0%)

Severe 0(0.0%)

Relationship with evaluation device, n (%) **

Definite 0(0.0%)

Probable 0(0.0%)

Possible 0(0.0%)

Probably Not 0(0.0%)

Not Related 0(0.0%)

Action taken, n (%) **



Safety Population

(N= 18)

None 0(0.0%)

Concomitant Medication 0(0.0%)

Non-Drug Treatment 0(0.0%)

Outcome, n (%) **

Recovered/resolved without sequelae 0(0.0%)

Recovered/resolved with sequelae 0(0.0%)

Worsened 0(0.0%)

Death 0(0.0%)

Unknown 0(0.0%)

12.3 DEATHS, OTHER SERIOUS ADVERSE EVENTS, AND OTHER SIGNIFICANT

ADVERSE EVENTS

No death, other SAE or were reported during the Evaluation but AE was reported in one

patient.

12.4 CLINICAL LABORATORY EVALUATION

Not performed in present Evaluation.

12.4.1Listing of Individual Laboratory Measurements by Subject and Each Abnormal

Laboratory Value

Not Applicable

12.4.2 Evaluation of Each Laboratory Parameter

Not Applicable

12.4.2.1 Laboratory Values over Time

Not Applicable.

12.4.2.2 Individual Subject Changes

Not Applicable



12.4.2.3 Individual Clinically Significant Abnormalities

Not Applicable

12.5 SAFETY CONCLUSIONS

In present evaluation, GLODERM 20L is found safe and well tolerable with good device

palatability while injection.

13. OVERALL CONCLUSION & DISCUSSION

The present clinical evaluation was performed in patients with facial wrinkles with objective to

assess the safety and performance of GLODERM 20L in subjects with facial wrinkle

improvement and incidence of all adverse events at 6 months and any systemic adverse event

at Furtinger DMD, Crnatkova 10, 10 000 Zagreb, Croatia. GLODERM 20L dermal filler is a

nonsurgical, physician-administered treatment for correction of facial wrinkles. There is well

evidence that GLODERM has good performance by filling the soft tissue of the dermis, adds

volume and diminishes the appearance of wrinkles and provide excellent look after treatment.

The best therapeutic results of using were observed with a dose 20 mg/ml, different volume

was injected in different areas of face. In present evaluation, GLODERM 20L was injected in

patients with same volume 0.4 ml in different areas of face and GAIS score data were analyzed

to assess effectiveness of GLODERM 20L formulation.

All patients involved in the study were Caucasian. Caucasians have sensitive skin

compared to asians. As skin type is key factor for photodamage and skin cancer risks, study of skin type helps in defining light-based treatments. The Fitzpatrick system is the

most frequently used classification technique for skin type. In present study, baseline data of

skin type were collected as per Fitzpatrick system.Patients with Type II Fitzpatrick skin

phototype (55.6%) were higher than other type.

Global Aesthetic Improvement scale score was considered as primary efficacy parameter to

measure the subject’s satisfaction with the wrinkle improvement. Study results revealed that

significant improvement was observed at 03 month follow up and remain consistent up to 06

month follow up for all patients. Mean Global Aesthetic Improvement scale Score (GAIS) was

improved significantly with mean GAIS score of 2.4 ± 0.51 (Mean improvement of 4.4) at 3

months follow up. Same mean value of GAIS score (2.4 ± 0.51) was also observed at 6 months

follow up. While evaluation of statistical significance by Wilcoxon Signed Ranks Test, p

(<0.001) value indicated highly significant improvement in mean GAIS Score (at 3 and 6

months follow up).

Philippe Kestemont et al. conducted study in France & Germany to evaluate facial

rejuvenation with treatment of Hyaluronic Acid Dermal Filler on 77 patients. Mean GAIS

Score at 3 months follow up (2.4 ± 0.6) in our study is equally improved and in line to results



of Philippe Kestemont et al, supporting literature based evidence. Mean GAIS of 2.4 ± 0.6 in

present study at 6 months follow up showed higher improvement compare to reference study

by Philippe Kestemont et al (mean GAIS score of 1.8±0.9 at 6 months follow up).

Study results interpreted clinically improved patient condition as 10 patients had much

improved (55.6%) and 8 patients had very much improved (44.4%) condition at 3 months

follow up which persisted at 6 month follow up, against worse or very much worst condition at

baseline. Proof of effectiveness was supported by statistically significant improvement in

Glabellar severity score as secondary parameter, at 03 month follow up and remain consistent

up to 06 month follow up for majority of patients. Mean Glabellar severity score was reduced

to 1.61 ± 0.61 at 3 months follow up which was 2.17 ± 0.79 at baseline and persisted same

value at 6 months follow up.

Number of patients with moderately deep wrinkles had reduced at 3 and 6 months follow up

(5.6%) compared to baseline (38.9%). However, none of patients with “No Wrinkles” at

follow up evaluation indicated that “Moderate Deep wrinkles” have been improved to “Just

perceptible Wrinkles” in those patients.

Treatment emergent adverse event was not reported in study. All patients reported expected

feel while Injection and none of patients have complication due to device failure, indicated

excellent Device Palatability in present study. In present evaluation, GLODERM 20L is found

safe and well tolerable with good device palatability while injection. Further, single dose

administration in a six month adds value because of patient convenience and compliance.

Results of present evaluation demonstrated significant improvement in GAIS score as well as

Glabellar severity at 3 and 6 months follow-up. Literature based evidence of efficacy and

confirmatory results of present evaluation for GLODERM 20L makes it suitable for use in

patients with facial wrinkles. However, as study is conducted in smaller population, further

studies with larger patient population are recommended to evaluate safety and efficacy of

GLODERM 20L and to have a chance to detect rare adverse event.



14. REFERENCES

1. American Society for Aesthetic Plastic Surgery. Cosmetic surgery national data bank

statistics 2012. Available from: http://www.surgery.org/sites/default/files/ASAPS-

2011-Stats.pdf. Accessed September 13, 2013.

2. Rzany B, Hilton S, Prager W, et al. Expert guideline on the use of porcine collagen in

aesthetic medicine. J Dtsch Dermatol Ges. 2010;8(3): 210–217.

3. Goldberg DJ. Legal ramifications of off-label filler use. Dermatol Ther.

2006;19(3):189–193.

4. Glogau RG, Kane MA. Effect of injection techniques on the rate of local adverse

events in patients implanted with nonanimal hyaluronic acid gel dermal fillers.

Dermatol Surg. 2008;34 Suppl 1:S105–S109.

5. Zielke H, Wölber L, Wiest L, Rzany B. Risk profiles of different injectable fillers:

results from the Injectable Filler Safety Evaluation (IFS study). Dermatol Surg.

2008;34(3):326–335.Clinical, Cosmetic and Investigational Dermatology 2013:6

6. Narins RS, Brandt FS, Lorenc ZP, Maas CS, Monheit GD, Smith SR. Twelve-month

persistency of a novel ribose-cross-linked collagen dermal filler. Dermatol Surg.

2008;34 Suppl 1:S31–S39.

7. Kono T, Kinney BM, Groff WF, Chan HH, Ercocen AR, Nozaki M. Randomized,

evaluator-blind, split-face comparison study of single cross-linked versus double cross-

linked hyaluronic acid in the treatment of glabellar lines.Dermatol Surg. 2008 Jun;34

Suppl 1:S25-30.

16. Appendices (Enclosed)

Documents

GLODERM 20L Evaluation Report 1.0 TITLE PAGE EVALUATION ... · Cross link Hyaluronic acid 20 mg/ml Title of Evaluation To assess the safety and performance of Dermal Fillers (GLODERM