A Prospective, Multicenter, Single-Arm Clinical Study Evaluating the Safety and Effectiveness of The Tixel Fractional System in The Treatment of Periorbital Wrinkles
Phase: NA
Conditions: Wrinkle, Periorbital, Tixel 2, Fractional, Resurfacing
Sponsor: Novoxel Ltd.

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A PROSPECTIVE, MULTICENTER, SINGLE-ARM CLINICAL 
STUDY EVALUATING THE SAFETY AND EFFECTIVENESS 
OF THE TIXEL FRACTIONAL SYSTEM IN THE TREATMENT 
OF PERIORBITAL WRINKLES 
 
 
Study Protocol No:  
CLN 0749 
 
Version: 
 
 
3.0 
 
Version Date: 
 
Jan 04, 2021 
 
Investigational Product: 
Tixel Fractional System  
 
 
 
Sponsor: 
 
 
Novoxel Ltd. 
 
 
 
 
43 Hamelaha St. 
 
 
 
 
Poleg Ind. Zone, Netanya,  
Israel 4250573 
 
Contact: 
 
 
Ifat Klein, PhD  
VP of Clinical Affairs 
ifat@novoxel.com 
 
Raphi Shavit 
Chairman, Novoxel Ltd. 
Raphi@novoxel.com 
  

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Contents 
1 Introduction 
4 
1.1
.
 
Study Background 
4 
1.1.1 
Treatment modalities..................................................................................... 5 
1.1.2 
Wrinkle Classification and Severity Assessment .............................................. 6 
1.1.3 
Fitzpatrick Wrinkle Classification Scale (FWCS) ............................................. 7 
1.2. 
Study Rationale 
8 
1.3. 
Study Device Description-The Tixel system 
8 
1.3.1. Safety Features of the Tixel 
9 
1.3.2. Expected Possible Side Effects 
9 
1.3.3. Benefits 
9 
1.3.4. Intended Use and Indications for Use 
10 
1.4. 
Study Objective 
10 
1.5
.
 
Study Design 
10 
1.6. 
Treatment parameters in the study and treatment area: 
10 
1.7. 
Study Endpoints 
10 
1.7.1. Primary Efficacy Endpoint 
10 
1.7.2. Secondary Efficacy Endpoint 
10 
1.7.3. Primary Safety Variable 
11 
1.7.4. Secondary Safety Variable 
11 
2 Study Population 
11 
2.1. 
Inclusion Criteria 
11 
2.2. 
Exclusion Criteria 
11 
3 STUDY FLOWCHART AND FOLLOW-UP ASSESSMENTS 
14 
4 Evaluation Tools 
16 
4.1. 
Fitzpatrick Skin Scale (FSS) 
16 
4.2. 
Fitzpatrick Wrinkle Classification Scale (FWCS) 
16 
4.3. 
Blinded Identification of 3-Month Images 
16 
4.4. 
Global Aesthetic Improvement Scale (GAIS) 
17 
4.5. 
Visual Analog Scale (VAS) 
17 
Additional patients’ Reported Outcomes (PROs) 
17 
5 Adverse Events Assessment and Reporting 
18 
5.1. 
Adverse Events Evaluation 
18 
5.2. 
Reporting Requirements 
18 
5.3. 
Contact email for SAE immediate reporting: 
18 

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5.4. 
Severity of Adverse Events 
18 
5.5. 
Relationship to the Study Device and/or Procedure 
19 
5.6. 
End of Study 
20 
5.6.1. Premature Termination or Suspension of the Study or a Study Site 
20 
5.7. 
Audits / Inspections 
20 
6 Statistical Methodology 
20 
6.1. 
Determination of Sample Size 
20 
6.2. 
Analysis Sets 
21 
6.2.1. Full Analysis Set (FAS) 
21 
6.2.2. Per Protocol Set (PPS) 
21 
6.3. 
Endpoints for Analysis 
21 
6.3.1. Primary Efficacy Endpoint 
21 
6.3.2. Secondary Efficacy Endpoint 
21 
6.4. 
Statistical Analysis for Safety Variables 
22 
6.4.1. Primary Safety Variable 
22 
6.4.2. Secondary Safety Variables 
22 
6.4.2.1. 
Visual Analog Scale (VAS) 
22 
6.4.2.1.1. Subject Downtime Assessment 
22 
6.4.3. Handling of Missing Data 
22 
6.4.4. Data Collection 
22 
6.5. 
Confidentiality of Data 
23 
 
 
  

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1 
INTRODUCTION 
1.1. Study Background 
Periorbital Wrinkles are an early manifestation of facial wrinkles1. They are lines or creases that 
form in the skin in the periorbital regions of the face. This is a significantly common multifactorial 
phenomenon, influenced by natural aging, photo aging (including UV exposure), facial 
expressions, skin type, hormonal status, genetic inclination, ethnicity, nutrition and various 
pathological disorders. These intrinsic factors contribute to epidermal thinning, loss of elasticity, 
skin fragility, etc. These are part of the human aging process, which affects the skin in its entirety 
and the facial skin in particular. Additional environmental factors, such as smoking, pollution and 
skin care, also affect periorbital wrinkles2.  
Wrinkles, in general, are reported to appear in people even younger than thirty years of age3. In 
the same manner as any other facial wrinkle, periorbital wrinkles increase gradually and affect 
one’s appearance and facial expression. Such effect also reflects on quality of life, due to impact 
on social interactions, occupational functioning and self-esteem in general4. Therefore, periorbital 
wrinkle reduction treatments are sought by many worldwide.  
Figure 1 - Conventional Segmentation of Periorbital Wrinkles 
 
 
1 “A Prospective Split-Face Comparative Study of Periorbital Wrinkle Treatments: Fractional Erbium Doped 
Yttrium Aluminum Garnet Laser Intense Pulsed Light, and Topical 0.1% Tretinoin Cream”, 
So Eun Park, Sang Seok Kim, Chul Woo Kim, Young Her, Department of Dermatology, Kangdong Sacred Heart 
Hospital, Hallym University College of Medicine, Seoul, 
1Department of Dermatology, Kangwon National University Hospital, Kangwon National University School of 
Medicine, Chuncheon, Korea 
2 https://www.mayoclinic.org/diseases-conditions/wrinkles/symptoms-causes/syc-20354927 
3 “Wrinkles”, Juan Manríquez, Daniela Majerson Grinberg, and Claudia Nicklas Diaz, Clinical Evidence 
2008;12:1711 
4 Gupta MA, Gupta AK. Photodamaged skin and quality of life: reasons for therapy. 
J Dermatol Treat 1996;7:261–264 

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Figure 2 - Various Severity Levels of Periorbital "Crow's Feet" Wrinkles1, by left-to-right, downward order of severity 
 
 
 
 
 
 
 
 
 
 
1.1.1 Treatment modalities  
Skin resurfacing or peel procedures have become an established non-surgical method for reducing 
certain skin imperfections such as wrinkles, dark spots, scars, or blemishes. Traditional fully 
ablative and fractional lasers are the most commonly used devices for skin resurfacing.  
The skin is composed of three layers: the epidermis, the dermis, and the hypodermis. The dermis 
contains well-organized and oriented collagen fibers that contribute to the firmness and 
smoothness of the skin. As people age, these collagen fibers reduce in number and become less 
organized, resulting in sagging and/or wrinkled skin. When esthetic procedures are scheduled for 
older adults, the rate of the epidermal turnover associated with a slower wound healing and less 

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effective desquamation (shading of outer layers of the skin), needs to be taken into consideration5. 
In most skin resurfacing procedures, an energy source (heat, radiofrequency energy, etc.) is used 
to selectively damage the skin and prompt a healing response that stimulates the growth of new 
collagen fibers in the dermis that are well-organized. The healing response and new collagen 
formation results in skin that is smoother and firmer. There are numerous traditional fully ablative 
and fractional lasers on the market today used for skin resurfacing. Traditional and fractional 
lasers differ in their method of treatment. Traditional lasers have a single beam that burns or 
damages all of the epidermis within the treatment area of the beam. Fractional lasers divide the 
beam into multiple smaller beams and treat only a “fraction” of the epidermis to affect changes 
in the deeper epidermis or dermis. This results in multiple small cores of laser damage surrounded 
by areas of healthy tissue. When compared to traditional lasers, fractional lasers deliver a more 
superficial treatment resulting in less risk for complications and reduced time for healing. 
However, this also means more treatments may be required to achieve the desired results 
especially in areas of deep lines or wrinkles. Healing times vary by amount of treatment, but 
fractional laser recovery time is typically one week compared to three to four weeks for traditional 
lasers. In the wake of the demonstrated safety and efficacy of laser skin resurfacing, multiple 
additional treatment modalities have been developed for this application including the use of 
radiofrequency (RF) energy. The fractionated radiofrequency results in epidermal and 
subepidermal ablation under the conductive pins that reproduces similar effects as a fractional 
CO2 laser with dermal heating, seen in the non-ablative lasers and devices6. The combination of 
epidermal ablation and dermal heating with radiofrequency, called sublative resurfacing in some 
studies, is suitable for skin types I–IV, for the treatment of skin laxity, wrinkles, enlarged pores, 
pigmented lesions, acne, telangiectasias, and scarring from trauma or acne. Subject recovery and 
downtime periods are significantly lower when compared with ablative laser healing times, with 
minimal adverse effects7. 
1.1.2 Wrinkle Classification and Severity Assessment 
Wrinkles are traditionally classified by most dermatologists into dynamic and static wrinkles.  
Static wrinkles are wrinkles that are visible when the facial musculature is rested (without facial 
expressions), and dynamic wrinkles are those that transiently appear when facial expressions are 
pronounced8.  
 
5 Ganceviciene R, Liakou A, Theodoridis A, Makrantonaki E, and Zouboulis C. Skin anti-aging strategies, 
Dermatoendocrinol. 2012 Jul 1; 4(3): 308–319. 
6 Hruza G, Taub AF, Collier SL, Mulholland SR. Skin rejuvenation and wrinkle reduction using a fractional 
radiofrequency system. J Drugs Dermatol. 2009;8(3):259–265. 
7 Mulholland RS, Ahn DH, Kreindel M, Paul M. Fractional Ablative Radio-Frequency Resurfacing in 
Asian and Caucasian Skin: A Novel Method for Deep Radiofrequency Fractional Skin 
Rejuvenation. Journal of Cosmetics, Dermatological Sciences and Applications. 2012;2(3):144–150. 
8 “Facial dynamics and emotional expressions in facial aging treatments”, Thierry Michaud, MD,1 Veronique 
Gassia, MD, 2 & Lakhdar Belhaouari, MD2 1 Private Practice, Mulhouse, France 2 Private Practice, Toulouse, 
France, Journal of Cosmetic Dermatology, 0, 1--13 

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1.1.3 Fitzpatrick Wrinkle Classification Scale (FWCS) 
Facial wrinkles are conventionally classified according to Fitzpatrick’s classification scale for 
facial wrinkles, described in the following Table 19,10,11: 
Table 1 - The Fitzpatrick Periorbital and Perioral Wrinkle Classification 
Class 
Description 
Score 
Description 
I 
Fine wrinkles 
1-3 
Mild: Fine texture changes 
with subtly accentuated skin 
lines. 
II 
Fine to moderate depth 
wrinkles, Moderate number of 
lines 
4-6 
Moderate: Distinct papular 
elastosis (individual papules 
with yellow translucency 
under direct lighting) and 
dyschromia 
III 
Fine to deep wrinkles, 
numerous lines, with or 
without redundant skin folds 
7-9 
Severe: Multipapular and 
confluent elastosis (thickened, 
yellow, and pallid) 
approaching or consistent with 
cutis rhomboidalis. 
 
  
 
9 “Pulsed carbon dioxide laser resurfacing of photo-aged facial skin”, Fitzpatrick, R. E., Goldman M. P., Satur, N. 
M., and Tope, W. D.  Arch. Dermatol. 132: 395, 1996. 
10 A Fractional Bipolar Radiofrequency Device Combined with a Bipolar Radiofrequency and Infrared Light Treatment 
for Improvement in Facial Wrinkles and Overall Skin Tone and Texture. 
11 https Fractionated microneedle radiofrequency for the treatment of periorbital wrinkles. 

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1.2. Study Rationale 
All current technologies available in worldwide markets nowadays do not offer full permanent 
clearance of periorbital wrinkles and cause certain levels of discomfort to the patients, 
accompanied with varying durations of downtime. Appearance is often improved to some degree 
of satisfaction of the subject, but not to the extent of complete solution for the condition. Due to 
the psychological impact of the conditions and its negative effect on life quality, better modalities 
are always sought. The Tixel technology aims to offer a more user friendly, radiation free, safety 
googles free, anesthesia/analgesia free al low device settings, toxic fumes free, safe and 
efficacious modality for fractional skin resurfacing of periorbital wrinkles, with results similar or 
better to currently market-available devices in the US12. 
1.3. Study Device Description-The Tixel system  
The Tixel family of products (for example Tixel 2 as in Figure 3) employs a thermo-mechanical 
technology that has been designed to provide a comparable clinical effect as a pulsed non-ablative 
laser and surface RF devices, which can be used as a treatment modality for a variety of dermal 
applications. The Tixel technology is based on the supply of contact-transferred heat from a high 
temperature (385°- 405°C) metal element (called a “tip”) consisting of an array of miniature 
pyramids. The tip (see Figure 4 and Figure 5) generates thermal coagulation in the tissue (usually 
200-300 microns deep) within 5 – 18 milliseconds pulse duration (contact duration between the 
tip and the skin), thus mimicking pulsed laser or surface RF action.  
The device has been cleared for marketing in multiple countries including European Union (EU), 
Australia, South Korea, Taiwan, Israel and other.  
Figure 3 - The Tixel 2 Device 
 
Figure 4 - The Tixel Standard Tip
 
 
 
12
The Tip’s 
treatment 
surface 

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Figure 5 - The Tixel Small Tip 
 
1.3.1. Safety Features of the Tixel 
The device is fully IEC-60601 compliant (safety and EMC). 
Over 750 Tixel devices have been sold to dermatologists and aesthetic doctors in the past 5 years, 
in over 25 countries. 
The Tixel device is designed with core safety, which is ensured via several aspects of its 
components: 
1. The device has an over-temperature automatic thermal shutdown in case of undesired 
temperature rise. This component is strictly hardware based.  
2. In case of a power fail, the Tip will always be retracted backwards to its home position 
detached from the skin. 
3. The system is always in a rested (home) position and activated only when the trigger is 
pressed.  
4. An air-cooled system for handpiece cooling which does not contain any type of liquid. 
5. Mechanical BIT (Built-In Test) – Before commencing operation mode, the system verifies 
free motion of the mechanical system.  
1.3.2. Expected Possible Side Effects 
In the same manner as all fractional skin treatment devices, there is risk of: Temporary swelling; 
Skin redness; Pain and/or burning sensation; Forming of large scabs or scabs lasting more than 
15 days; Significant/thick skin peeling; Post Inflammatory Hyperpigmentation (PIH); Hypo-
pigmentation; Sensitivity to sun exposure; Local burns; Scars, edema, erythema and watery eye 
for few hours after the treatment.  
1.3.3. Benefits 
A possible benefit of using Tixel is the potential for improvement in wrinkle severity. Additional 
potential benefits of improving the appearance of wrinkles could include enhanced well-being, 
with improved satisfaction with the appearance of less peri-orbital wrinkles or the perception of 
a having a more youthful appearance. 
The Tip’s 
treatment surface 
 

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1.3.4. Intended Use and Indications for Use 
Skin rejuvenation by fractional non-ablative treatment of the skin. 
The Tixel System is intended for cutaneous procedures requiring coagulation of soft tissue and 
skin resurfacing procedures. Treatments are performed by physicians and trained clinicians.  
1.4. Study Objective 
To demonstrate the safety and performance of the Tixel fractional system for treatment of 
periorbital wrinkles. 
 
1.5. Study Design 
A Prospective, Multicenter, Single-Arm Clinical Study of 51 subjects who are seeking a 
procedure to reduce the appearance of the periorbital wrinkles, and meet study eligibility criteria, 
and have provided informed consent will be enrolled in the study. Up to 5 investigational centers 
in Israel and the United States will participate in the recruitment. Each study subject will receive 
four treatments with Tixel 2 in a monthly interval. Follow-up will occur at 1 month and 3 months 
following the last treatment.  
1.6. Treatment parameters in the study and treatment area:   
1. Protrusion- between 400-600 microns, 
2. Pulse duration- between 10-12 milliseconds (lower for skin-type V e.g. 6-8).  
3. Single or double pass, except crow’s feet which can be treated in crisscross when severe 
wrinkles exist. 
4. The treated area outside of the orbital rim should encompass below and above the brow, 
lower eyelid and at beyond (1-2 cm at 45 degrees above and below) the most lateral 
aspect of the most lateral wrinkle.  
5. Treatment directly on the eyelid is forbidden.  
1.7. Study Endpoints 
1.7.1. Primary Efficacy Endpoint 
Comparison of the proportion of subjects with a ≥ 1-score improvement on the FWCS at the 3-
month visit compared to baseline as determined by at least 2 out of 3 blinded Independent 
Photographic Reviewers.  
The study design assumes a 65% success rate of subjects with a ≥ 1-score change on the FWCS, 
therefore, greater or equal to 65% of subjects must be rated with a ≥ 1-score improvement 3 
months after treatment and must be statistically significantly. 
1.7.2. Secondary Efficacy Endpoint 
Assessment of improvement at each visit compared to baseline by the handling physician. 
The following assessment methods will be applied (frontal clinical assessment or by images): 
• 
FWCS - Fitzpatrick Wrinkle Classification Scale 
• 
GAIS - Global Aesthetic Improvement Scale Assessment 
Patients’ Reported Outcomes (PROs): 
• 
Subject Satisfaction Questionnaire 

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1.7.3. Primary Safety Variable 
Evaluation of related adverse events up to the 3-months FU visit. 
1.7.4. Secondary Safety Variable 
• 
Evaluation of the pain and discomfort of the treatment as reported by the subject on 
a visual analog scale (VAS). 
• 
Subject Subjective Downtime Assessment. 
2 
STUDY POPULATION 
2.1. Inclusion Criteria 
1. Male or female 35-70 years old diagnosed with clinically evident static periorbital wrinkles. 
2. Willingness and ability to comply with all required study activities including returning for 
follow-up visits and protocol requirements. 
3. The subject is able to provide written informed consent and perform the study’s activities 
according to HIPAA guidelines and/or Israeli law, depending on each specific study site. 
4. Fitzpatrick wrinkle score of 3-7 in the peri-orbital areas per the treating investigator and 
clinically noticeable wrinkles in the treating area.   
5. Stable body weight during the study period.   
6. Skin Type I – V as per Fitzpatrick Skin Scale.   
 
2.2. Exclusion Criteria 
1. Past treatment with Tixel device. 
2. The subject may not undergo treatment by the Tixel device according to the device’s contra-
indications for use, as defined in the User Manual and in the Instructions for Use and by any 
other labeling of the device.  
3. Subjects who, in the investigator's opinion, have a history of poor cooperation, 
noncompliance with medical treatment, or unreliability. 
4. Female subjects who are pregnant, or planning to become pregnant, or have given birth less 
than 3 months ago or are lactating.  
5. Subjects with significant exposure to critical amounts of ultraviolet light (Sun-tan).  
6. Subjects who have had the following treatments: 
a. a cosmetic procedure to improve peri-orbital rhytides (i.e. periorbital or eyelid/eyebrow 

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surgery, brow lift, CO2/Erbium/similar laser/fractional resurfacing, radiofrequency 
treatment) within 12 months  
b. prior facial treatments with laser, surgical, chemical or light-based facial treatments 
within the previous 12 months, over the periorbital area including botulinum toxin 
injections, microdermabrasion or prescription level glycolic acid treatments. 
c. Injectable filler in cheeks (mid face) temples and in the upper face area to be treated 
within 12 months of investigation. 
7. Any subject who have visible scars or other visible changes over the treated areas that may 
affect evaluation of response and/or quality of photography. 
8. Subjects with any type of active cut, wound, inflammation, lesion (benign, premalignant or 
malignant) or active bacterial, viral, fungal, or herpetic infection on the skin on the 
designated treatment sites or in close proximity to it. 
9. Existing or history of the following (when discussing skin conditions, refers only to the 
periorbital sites): 
a. skin malignancy, or any diagnosis of suspected malignancy 
b. Collagen or vascular or bleeding disease 
c. Immunosuppression or autoimmune disease 
d. Erythema with or without blistering 
e. History of post inflammatory hyperpigmentation. 
f. Active Acne Vulgaris, HSV-1, or any existing skin condition/disease that in the 
investigator’s opinion would interfere with the evaluation of the safety of the study 
treatment and evaluation.  
g. Any skin pathology which can induce bullous lesions, urticaria, or demonstrate a 
Koebner phenomenon (psoriasis, lichen planus, etc.). 
h. Any disease that inhibits pain sensation 
i. History of keloid formation, or hypertrophic scarring 
j. Conditions affecting healing rate (i.e. diabetes mellitus I or II, vascular condition, etc.) 
k. neuromuscular disorders 
10. Subjects who have used, within 30 days, any medication that can cause dermal 
hypersensitivity or affect skin characteristics over the treated area (i.e. topically applied 
Retinoids, Hydroquinone, Chemical peel of any strength: glycolic acid, lactic acid, salicylic 

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acid) 
11. Subjects who have used, systemic treatment which may induce dyspigmentation, such as 
amiodarone, clofazinmine, minocycline or chloroquine. 
12. Subjects currently taking or have taken an oral retinoid in the past six months; Subjects 
currently taking long-term oral steroid treatment.  
13. Concurrent therapy that, in the principal investigator's opinion, would interfere with the 
evaluation of the safety or efficacy of the study treatment. 
14. Subjects who anticipate the need for major surgery or overnight hospitalization during the 
study that can affect the study schedule or treatment evaluation. 
15. Enrollment in any active study involving the use of investigational devices or drugs. 
16. Any other cause per the principal investigator’s discretion. 
 

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Study visits procedures (see Table 2) 
3
STUDY FLOWCHART AND FOLLOW-UP ASSESSMENTS 
Table 2: Study Flowchart and Follow-Up Assessments 
Procedure 
Visit 1 
(V1) 
Tx 1b 
Phone 
call visit 
Visit 2 
(V2) 
Tx 2  
Visit 3 
(V3) 
Tx 3  
Visit 4 
(V4) 
Tx 4  
Visit 5  
1 month 
Follow-
up  
1 
Visit 6 
3 
months 
Follow-
up  
2 
V1 
V1 + 3d 
(± 1d) 
V1 + 
4wk 
(± 7d) 
V2 + 4wk 
(± 7d) 
V3 + 4wk 
(± 7d) 
V4 + 
4wk 
(± 7d) 
V4 + 
12wk 
(± 7d) 
Subject Screening, 
Enrolment 
Procedure & 
Informed Consentd, 
Post treatment care 
instructions sheet 
X 
 
 
 
 
 
 
Weight and Height 
X 
 
 
 
 
 
 
Weight 
 
 
X 
X 
X 
X 
X 
Facial 
dermatological skin 
examination   
X 
 
X 
X 
X 
X 
X 
Inclusion/ Exclusion 
criteria 
X 
 
 
 
 
 
 
Medical/Surgical 
history from the last 
five years 
X 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
Fitzpatrick Skin 
Scale (FSS) 
X 
 
 
 
 
 
 
Concomitant 
Therapy/Medication 
Xa 
 
X 
X 
X 
X 
X 
Verbal Inquiry 
regarding pregnancy 
X 
 
X 
X 
X 
X 
X 
Photography of 
Treatment Area(s) – 
prior to treatment 
X 
(baselin
e  (  
 
 
 
 
X 
X 
Investigational 
Device Treatment 
X 
 
X 
X 
X 
 
 
GAIS Assessment 
by the Investigator 
 
 
 
 
 
X 
X 
FWCS Assessment  
Xc 
 
 
 
 
X 
Xc 
Subject VAS Pain 
assessment 
X 
 
X 
X 
X 
 
 
Subject Subjective 
Downtime 
X 
 
X 
X 
X 
 
 

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Procedure 
Visit 1 
(V1) 
Tx 1b 
Phone 
call visit 
Visit 2 
(V2) 
Tx 2  
Visit 3 
(V3) 
Tx 3  
Visit 4 
(V4) 
Tx 4  
Visit 5  
1 month 
Follow-
up  
1 
Visit 6 
3 
months 
Follow-
up  
2 
V1 
V1 + 3d 
(± 1d) 
V1 + 
4wk 
(± 7d) 
V2 + 4wk 
(± 7d) 
V3 + 4wk 
(± 7d) 
V4 + 
4wk 
(± 7d) 
V4 + 
12wk 
(± 7d) 
Assessment 
Questionnaire – 
given to subject 
Collect Subject 
Subjective 
Downtime 
Assessment 
Questionnaire 
(regarding skin 
erythema, redness 
and scabs) 
 
 
X 
X 
X 
X 
 
Adverse Events 
X 
 
X 
X 
X 
X 
X 
Subject Compliance 
X 
 
X 
X 
X 
X 
X 
Post Treatment Care 
Instructions 
X 
 
X 
X 
X 
 
 
Subject Experience 
Questionnaire 
 
 
 
 
 
X 
X 
Post treatment 
reaction assess via 
phone 
 
X 
 
 
 
 
 
a. 
At Screening, the review of concomitant medications should include those taken within the past year. 
b. All assessments on treatment days are to be performed prior to treatment; the assessments performed prior to 
Treatment 1 will be designated as Baseline. 
c. 
Blinded assessment performed in addition to physician assessment. Shall be performed at the end of the subject's 
activities. 
d. First visit may be split into two separate visits, with no more than 7 days between the two separate visits: part I: 
screening, enrollment, post treatment care instructions sheet and informed consent, and part II: rest of visit 
content. 
 

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4 
EVALUATION TOOLS 
The following evaluation tools will be used in this study: 
4.1. Fitzpatrick Skin Scale (FSS) 
Assessment of subject’s skin color will be determined prior to study procedure by the Investigator 
using the FSS. The scale delineates skin color into the categories as shown in Table 3- Fitzpatrick 
Skin Scale Evaluation. See שגיאה! מקור ההפניה לא נמצא..
. 
Table 3- Fitzpatrick Skin Scale Evaluation 
Skin Type 
Description 
Type I  
White skin that never tans and always burns easily 
Type II 
White skin that tans slightly and always burns easily 
Type III 
Light brown skin that tans gradually and can burn moderately 
Type IV 
Moderately brown skin that tans well and burns slightly 
Type V 
Dark brown skin that tans profusely and burns rarely 
Type VI 
Black skin with deep pigmentation that never burns 
 
4.2. Fitzpatrick Wrinkle Classification Scale (FWCS) 
Assessment of subject wrinkles will be performed by the Investigator and in addition, will be 
performed by three board-certified independent dermatologists or plastic surgeons (“Raters”), 
using the Fitzpatrick Wrinkle Classification Scale (FWCS) categories as shown in Table 4. The 
FWCS is a clinically validated assessment tool used to assess skin wrinkle severity and elastosis 
on a scale from 1 through 9, where the lower score is considered better.  
The investigator will assess FWCS at baseline, 1-months and 3 months follow up visit, while the 
raters will assess only at baseline and 3 months follow up visit. 
4.3. Blinded Identification of 3-Month Images 
Assessment of each subject’s baseline and 3-month follow-up images viewed simultaneously will 
be performed by the Independent Photographic Reviewers (“Raters”) who will be blinded to the 
study subject’s visit (baseline and 3-month follow-up visit). Each rater will view each subject’s 
randomized baseline and 3-month follow-up images and assess which set of images represent the 
subject’s post-treatment images. Each photograph will have a unique identification number, but 
the sets of images will not be arranged in any specific order. The Raters will assign a single FWCS 
score per subject at each time point. A subject will be considered a success if at least 2 out of the 
3 Raters correctly identify the 3-month images and the FWCS score is ≥1. 
 
 

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Table 4- Fitzpatrick Wrinkle and Elastosis Scale 
Class 
Description 
Score 
Description 
I 
Fine wrinkles 
1-3 
Mild: Fine texture changes 
with subtly accentuated skin 
lines. 
II 
Fine to moderate depth 
wrinkles, Moderate number of 
lines 
4-6 
Moderate: Distinct papular 
elastosis (individual papules 
with yellow translucency 
under direct lighting) and 
dyschromia 
III 
Fine to deep wrinkles, 
numerous lines, with or 
without redundant skin folds 
7-9 
Severe: Multipapular and 
confluent elastosis (thickened, 
yellow, and pallid) 
approaching or consistent with 
cutis rhomboidalis. 
 
4.4. Global Aesthetic Improvement Scale (GAIS) 
Treatment results compared to pre-treatment. The Investigator will grade the overall 
improvement of treatment area as indicated in Table 5 by comparing the subject’s appearance in 
each of the follow up visits, against a photograph taken prior to procedure. 
Table 5- Global Aesthetic Improvement Scale Evaluation (GAIS) 
Score  
1 
2 
3 
4 
Assessment 
0-25% - Poor 
response  
25-50% - Fair 
response 
50-75% - Good 
response 
75-100% - 
Excellent response 
 
4.5. Visual Analog Scale (VAS) 
The study subjects will be asked to complete a 10-point Visual Analog Scale (VAS) for the 
following assessments:  
Level of pain and discomfort associated with study procedure – to be completed by the subjects 
on the day of the procedure, immediately following the procedure. Scoring will consist of making 
a mark on a 10-points scale. Each line will be awarded a score of 0 - 10 according to the level of 
pain when 0 is no pain and 10 is the maximum pain possible. See 
ש.אצמנ אל הינפהה רוקמ !האיג.
. 
Additional patients’ Reported Outcomes (PROs) 
• Subject Subjective Downtime Assessment - Downtime defined as the period of time 
following the procedure during which the subject felt unable/unwilling to go out in public 
due to edema and/or erythema. The determination of “downtime” is measured in hours or 
days following the procedure. This will be recorded following every treatment visit (see שגיאה! מקור ההפניה לא נמצא.
.
).   
• Subject experience questionnaire will be filled by the subject at each follow-up visits (see שגיאה! מקור ההפניה לא נמצא.
.
). 
 

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5 
ADVERSE EVENTS ASSESSMENT AND REPORTING 
5.1. Adverse Events Evaluation 
Safety evaluation for this study includes an interview with the study subject at each visit by the 
Investigator or Research Coordinator to elicit information about any medical occurrence that 
meets the definition of Adverse Event. This information will be documented in CRF without 
regard for cause or relation to device and/or procedure. In addition, study subjects will be 
instructed to report all of complications experienced post study procedure to the site personnel as 
soon as they occur/are observed. It is the Investigator’s responsibility to determine seriousness, 
severity, and relatedness of the Adverse Event to the device and procedure using the definitions 
below. 
All adverse events, anticipated or unanticipated, will be monitored until they are adequately 
resolved or explained. 
5.2. Reporting Requirements 
All adverse events (AEs) observed by study subjects, investigators, or other study staff from first 
exposure to the study product through last study follow-up visit will be recorded. If a device 
related AE, SAE, or unanticipated serious device related effect is ongoing at the final study visit, 
the subject will be followed until resolution, until the condition stabilizes, until the event is 
otherwise explained, or the subject is lost to follow-up. The investigator should make every effort 
to ensure that follow-up includes any supplemental investigations as may be indicated to 
elucidate, as completely as practical, the nature and/or causality of the AE or SAE. This may 
include unscheduled follow up visits for AE assessment.  
Study subjects will be instructed to report all AEs to the clinical study staff. AE information will 
be collected throughout the study and recorded on CRFs. 
5.3. Contact email for SAE immediate reporting:  
Study personnel must report to the sponsor any SAE or UADE by telephone as well as by email, 
as soon as possible and no later than 24 hours of the awareness of the event. The initial telephone 
notification (or email) should be followed by a written report (Serious Adverse Event report form) 
describing the SAE or UADE and signed by the investigator.  
Study personnel must forward follow-up information and complete event report to the sponsor as 
the event continues and/or subsides/resolves, or in the case of permanent impairment, until the 
event stabilizes, and the overall clinical outcome has been ascertained. The SAE report (initial 
and/or follow up) should be sent via e-mail to the sponsor at Safety@novoxel.com.  
5.4. Severity of Adverse Events 
The severity of adverse events will be categorized using the following criteria: 
• Mild: easily tolerated by the subject, causing minimal discomfort and not interfering with 
everyday activities. These events generally do not require treatment. 
• Moderate: sufficiently discomforting to interfere with normal everyday activities. These 
vents are usually relieved by simple therapeutic measures. 
• Severe: prevents normal, everyday activities. These events may require systemic drug 
therapy or other medical treatment. 

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5.5. Relationship to the Study Device and/or Procedure 
Each AE should be assessed for its relationship to the device or procedure as identified as follows: 
Device: This category should be restricted to adverse events directly attributable to the effect of 
the device. 
Procedure: A procedure is any activity that supports the usage of the device.  
Use the following categories for assigning the certainty of the relatedness: 
Definitely Related: An AE is definitely related if it is obvious, certain or there is little doubt 
regarding the relationship. 
Probably Related: An AE is probably related if cannot be explained by a concomitant illness or 
by other medicinal products. 
Possibly Related: An AE is possibly related if it is capable of being related but relatively unlikely. 
Not Related: An AE is not related if it is determined that there is no plausible association. 
Unknown: Use this term if there is insufficient information to determine if the AE is related to 
the device or procedure. 
 

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5.6. End of Study 
The end of study will be defined as completion of all study visits by all enrolled subjects. If a 
device-related AE, SAE, or unanticipated serious device-related effect is ongoing at the final 
study visit, the subject will be followed until resolution, until the condition stabilizes, until the 
event is otherwise explained, or the subject is lost to follow-up.  
Study closure visits may be conducted at all clinical sites in order to review record retention 
requirements, device disposition requirements, etc., with site personnel. The Sponsor may choose 
to conduct the closure visit via telephone contact if appropriate. 
5.6.1. Premature Termination or Suspension of the Study or a Study Site 
Novoxel Clinical/RA department may terminate the participation of a center before the 
completion of the investigation due to one or more of the following reasons: 
• The investigator is unable or unwilling to continue the investigation, 
• The investigator is unable or unwilling to comply with the protocol requirements, 
• The Monitoring audit results indicate study staff non-compliance. 
The Sponsor may also terminate a study prematurely in case of: 
• Safety concerns, 
• Inability to obtain the number of subjects required by the protocol, 
• Any other reason, pre-defined within the protocol. 
5.7. Audits / Inspections 
The Sponsor, their designee, and the reviewing IRB may monitor or audit the study centers. 
Likewise, regulatory authorities may inspect Sponsor or study vendors/CRO files or any study 
center to evaluate the conduct of the study. The Investigator must allow access to the subject files 
and inspection of their clinical research protocol procedures when requested. 
6 
STATISTICAL METHODOLOGY 
This section describes the statistical analyses foreseen at the time of study planning. Any 
deviations from planned analyses, the reasons for such deviation, and all alternative or additional 
statistical analyses that may be performed before database close will be summarized in the 
Clinical Study Report. 
6.1.  Determination of Sample Size 
• The objective of this study is to demonstrate that study participants positively respond to 
the Tixel, thus the primary endpoint will be assessed via the percentage of study 
participants that demonstrated an improvement in the FWCS from baseline to the 3-month 
visit.  
• An improvement is clinically important when FWCS ≥ 1 score.  
The sample size calculation is based on the rate of subjects for which a score improvement 
on the FWCS at 3-month compared to baseline (success rate). The success rate is expected 
to be 65%. 

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When the sample size is 44, a two-sided 95% confidence interval for a single proportion using 
the large sample normal approximation will extend 0.14 from the observed proportion for an 
expected proportion of 0.65. 
To account for possible missing data (up to 15% attrition), 51 subjects will be enrolled.  
• Total N: up to 51 study participants 
A study investigating the effects of RF device on the improvement of appearance of peri-orbital 
wrinkles (VIVACE K150409 Class II FDA approved device) utilized a FWCS cutoff as 60%, 
supporting this value in the present sample size computation.  
6.2.  Analysis Sets 
The full analysis set (FAS) will be used for analysis of safety parameters and secondary endpoints 
in this study. 
6.2.1. Full Analysis Set (FAS) 
All subjects enrolled in the study who received at least one treatment, will be included in the FAS.   
6.2.2. Per Protocol Set (PPS) 
The PPS is the subset of subjects in the FAS without major protocol deviations and only if 
received the full treatments and have quality photos in the baseline and in the 3 months follow-
up visit. Major protocol deviations will be decided and finalized by an independent reviewer prior 
to database lock. The primary efficacy analyses and also the secondary efficacy endpoints (in 
addition to the FAS) will be analyzed on the PP population.  
6.3.  Endpoints for Analysis 
6.3.1. Primary Efficacy Endpoint 
The primary efficacy endpoint is the comparison of the proportion of subjects (i.e. percentage of 
treatment responders) with a ≥ 1-score improvement on the FWCS at the 3- month visit, as 
compared to baseline as determined by at least 2 out of 3 blinded Independent Photographic 
Reviewers. The study design assumes a 65% success rate of subjects with treated wrinkles with 
a ≥ 1-score change on the FWCS; therefore, even or greater than 65% of subjects must be rated 
with a ≥ 1-score improvement 3 months after treatment. and must be statistically significantly.  
6.3.2. Secondary Efficacy Endpoint 
shall be assessed and quantified by the handling physician. 
The following assessment methods will be applied (frontal clinical assessment or by images): 
• 
FWCS - Fitzpatrick Wrinkle Classification Scale (at each FU visit) 
• 
GAIS - Global Aesthetic Improvement Scale Assessment ( at each FU visit) 
Patients’ Reported Outcomes (PROs): 
• Subject Experience and Satisfaction Questionnaire (in the 2 FU visits) 
• Subject Subjective Downtime Assessment (following each treatment visit) 

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6.4.  Statistical Analysis for Safety Variables 
6.4.1. Primary Safety Variable 
The primary safety variable is the evaluation of adverse events up to the 3-month visit after 
treatment. Adverse events reported at each scheduled study visit will be summarized. A 
descriptive analysis including type, onset after treatment, duration, severity, and relationship to 
study device and/or procedure will be provided.  
6.4.2. Secondary Safety Variables 
6.4.2.1. 
Visual Analog Scale (VAS) 
Evaluation of the pain and discomfort of the treatment as reported by the subject on a 10-point 
visual analog scale (VAS). Results of the VAS on a scale of 0 (no pain) to 10 (most severe pain) 
will be summarized descriptively utilizing mean, standard deviation, minimum, maximum, 
median, and the 95% confidence interval of the mean.  
6.4.2.1.1. 
Subject Downtime Assessment 
Downtime defined as the period of time following the procedure during which the subject felt 
unable/unwilling to go out in public due to edema and/or erythema. The determination of 
“downtime” is measured in hours or days following the procedure. This will be recorded 
following each treatment visit. See appendix D.   
6.4.3.  Handling of Missing Data 
• Every effort will be made to obtain all FWCS data at month-3 evaluation from all 
subjects  who have been enrolled to minimize missing data. However, in the event when 
there is missing data the following imputation methods will be used.  
  
• Imputation using mean values: the missing FWCS value will be replaced by the average 
of non-missing FWCS values at month-3 in the same treatment group by the same 
evaluator. 
• Imputation using baseline values: the missing FWCS value will be replaced by the 
subject's baseline FWCS value by the same evaluator. 
• The MMRM model (Mixed-effect Model for Repeated Measures), which is 
based on MAR (missing at random) assumption will be applied to all enrolled 
subjects. 
 
Sensitivity analyses will be applied for testing the effect of the imputation on 
the treatment effect. This will show the influence of the imputation on the 
study results. 
 
6.4.4. Data Collection 
Subject demographic information, procedural data, adverse events, device observations, and 
study required assessments will be documented on the CRFs. Study subjects will complete Visual 
Analog Scale (VAS) and Downtime assessment following each treatment visit and Experience 
questionnaire  at each follow-up visit. 

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6.5. Confidentiality of Data 
The Principal Investigator will oversee the conduct of the study and all data will be kept 
confidential. Confidentiality will be maintained by using subject identification numbers instead 
of names. Informed consent forms, data collection sheets and records, linking a subject’s name 
with their ID number will be maintained in a locked cabinet or locked office. Information to be 
stored on the computer will be identified by subject ID and will be password protected. Data 
disclosed outside the study team will be de-identified or will only include general group 
demographic information. Protected Health Information and/or identifiable study data will not be 
shared with anyone outside the study team or Health System, with the exception of the study 
sponsor, and federal regulators/ institutional officials for the purposes of auditing.