A Randomized, Masked (Evaluator), Controlled, Prospective Study Evaluating the Effectiveness and Safety of the Tixel® Medical Device, Versus LipiFlow® in the Treatment of Meibomian Gland Dysfunction
Phase: NA
Conditions: Meibomian Gland Dysfunction, Dry Eye Syndromes, Dry Eye
Sponsor: Novoxel Ltd.

Clinical Protocol Number: CLN 0858 Rev. 007 
18-Jan-2023 
Page 1 of 19 
 
A RANDOMIZED, MASKED (EVALUATOR), CONTROLLED, 
PROSPECTIVE STUDY EVALUATING THE 
EFFECTIVENESS AND SAFETY OF THE TIXEL MEDICAL 
DEVICE, VERSUS LIPIFLOW IN THE TREATMENT OF 
MEIBOMIAN GLAND DYSFUNCTION – STUDY SYNOPSIS 
Clinical Investigational Plan (CIP): 
CLN 0858 
Version: 
7.0 
Version Date: 
18-Jan-2023 
Investigational Product: 
Tixel Fractional System 
Class of Medical Device (EU MDR): 
IIa 
Medical Device Classification (US FDA): II 
Sponsor: 
Novoxel Ltd. 
43 Hamelaha St. 
Poleg Ind. Zone, Netanya,  
Israel 4250573 
Contacts (Novoxel Ltd.): 
Ifat Klein, PhD  
VP of Clinical Affairs 
ifat@novoxel.com 
Raphi Shavit 
Chairman 
Raphi@novoxel.com  
 
 

Clinical Protocol Number: CLN 0858 Rev. 007 
18-Jan-2023 
Page 2 of 19 
 
1. STUDY SYNOPSIS 
Study Name  
A Randomized, Masked (Evaluator), Controlled, Prospective Study 
evaluating the Effectiveness and Safety of the Tixel® Medical Device, 
Versus LipiFlow® in the Treatment of Meibomian Gland Dysfunction 
Study Device  
Tixel C 
Stage of 
Development  
Pivotal study to support an indication for use of treatment of Meibomian 
Gland Dysfunction  
General Design 
The study includes 2 stages: stage 1 is the main pivotal protocol, and stage 2 
is an extension study for a sub-group population which completed the main 
protocol, was treated with the Tixel device and meets specific criteria of 
clinical benefit (specified in the description of stage 2 below).   
Stage 1- the main protocol 
Design 
• Randomized, open-label study comparing the Tixel device to 
LipiFlow System.  
• Up to 110 patients (220 eyes) to be randomized in up to 6 clinical sites 
in the United States.  
• Evaluators will be masked as to the randomization assignments.  
• Both eyes will receive the same randomized assignment and both eyes 
of each patient will be evaluated at all time points. 
• Data from both eyes will be using in the statistical analysis. 
 The random-effects model adjusts the standard error (SE) and the confidence 
interval (CI) for within-person correlation between eyes. 
Objective  
Evaluate the safety and effectiveness of the Tixel C device in adults with 
Meibomian Gland Dysfunction (MGD). 
Primary 
Effectiveness 
Endpoint 
Change from baseline to the 4-weeks follow-up exam in Tear Break Up Time 
(TBUT). 
Secondary 
Effectiveness 
Endpoints 
• Change from baseline in patient symptoms using Ocular Surface Disease 
Index (OSDI) at 4-weeks and 12-weeks follow-up exam. 

Clinical Protocol Number: CLN 0858 Rev. 007 
18-Jan-2023 
Page 3 of 19 
 
• Change from baseline to 4-weeks and 12-weeks follow-up exam in 
Meibomian Gland Score (MGS). 
• Change from baseline to 12-weeks follow-up exam in Tear Break Up Time 
(TBUT). 
Key Safety 
Endpoint  
Comparison of the incidence of Ocular Adverse Events for the two treatment 
arms.  
Secondary 
Safety 
Endpoints 
• The evaluation of discomfort and pain during treatment. 
• Changes from baseline following treatment for the test and control devices 
for the following assessments:  
 Ocular Surface Staining.  
 Intraocular Pressure. 
 Best corrected distance Visual acuity. 
Population 
Adult patients with symptoms of evaporative dry eye/MGD who do not 
respond adequately to conservative treatment options such as ocular 
lubricants. 
Sample size 
Up to 110 patients (220 eyes), 55 patients per device to be enrolled at up to 6 
study sites in the US, will serve as sample size to investigate whether the Tixel 
C device is non-inferior to the LipiFlow system in terms of change in TBUT 
from baseline to 4 weeks following the last treatment.  
Sample size rationale: 
The sample size calculation is based on the primary effectiveness endpoint. 
Specifically, the sample size calculation was based on the non-inferiority with 
a 2.5 seconds’ margin of the change from baseline in TBUT score as assessed 
by a masked rater at 4 weeks follow-up for Tixel versus LipiFlow. The 
expected standard deviation of the difference in change is 4.5 seconds.  
The calculation assumes the worst case scenario that the TBUT of both eyes 
of subjects are completely correlated (r=1).   
Sample size justification: 
When the sample size in each group is 44, a two group one-sided 0.05 
significance level t-test will have 80% power to reject the null hypothesis that 
the test and standard are not non-inferior (the difference in means, μT-μL, is 
2.5 s or farther from zero in the same direction) in favor of the alternative 

Clinical Protocol Number: CLN 0858 Rev. 007 
18-Jan-2023 
Page 4 of 19 
 
hypothesis that the means of the two groups are non-inferior, assuming that 
the expected difference in means is 0 and the common standard deviation is 
4.5 s. 
Assuming a 20% drop-out rate (a relatively high rate is currently assumed due 
to Covid-19 uncertainty), 55 patients will be enrolled in each group ensuring 
a sample size of 44 patients per group. 
Inclusion Criteria  
1. Age 22 years and older of any gender or race. 
2. Provision of written informed consent prior to study participation.  
3. Willingness and ability to return for all study visits. 
4. Reports dry eye symptoms for three months prior to the study. 
5. Ocular Surface Disease Index (OSDI) score between 23-79. 
6. Tear break-up time (TBUT) <10 seconds in both eyes.  
7. Agreement/ability to abstain from dry eye/MGD medications for the 
time between the treatment visit/s and the final study visit. Ocular 
lubricants are allowed if no changes are made during the study. 
8. Reports having to use artificial tears or lubricants regulatory over the 
past month to relieve dry eye symptoms. 
9. Meibomian gland obstruction in both eyes based on a total Meibomian 
Gland Secretion Score ≤12 in each eye. 
10. At least 15 glands in each lower eyelid should be expressible, with a 
sterile cotton swab, at the slit lamp. 
Exclusion Criteria 
1. History of ocular surgery including intraocular, oculo-plastic, corneal 
or refractive surgery within 6 months. 
2. Patients with giant papillary conjunctivitis. 
3. Patients with punctal plugs or who have had punctal cautery. 
4. Ocular injury or trauma, chemical burns, or limbal stem cell deficiency 
within 3 months of the baseline examination. 
5. Active ocular herpes zoster or simplex of eye or eyelid or a history of 
these any time. 
6. Patients who are aphakic. 
7. Cicatricial lid margin disease identified via slit lamp examination, 
including pemphigoid, symblepharon, etc. 

Clinical Protocol Number: CLN 0858 Rev. 007 
18-Jan-2023 
Page 5 of 19 
 
8. Active ocular infection (e.g., viral, bacterial, mycobacterial, 
protozoan, or fungal infection of the cornea, conjunctiva, lacrimal 
gland, lacrimal sac, or eyelids including a hordeolum or stye). 
9. Active ocular inflammation or history of chronic, recurrent ocular 
inflammation within prior 3 months (e.g., retinitis, macular 
inflammation, choroiditis, uveitis, iritis, scleritis, episcleritis, 
keratitis). 
10. Ocular surface abnormality that may compromise corneal integrity 
(e.g., prior chemical burn, recurrent corneal erosion, corneal epithelial 
defect, Grade 3 corneal fluorescein staining, or map dot fingerprint 
dystrophy). 
11. Lid surface abnormalities (e.g., entropion, ectropion, tumor, edema, 
blepharospasm, lagophthalmos, severe trichiasis, severe ptosis) that 
may affect lid function in either eye. 
12. Anterior blepharitis (staphylococcal, demodex or seborrheic grade 3 
or 4). 
13. Systemic disease conditions that cause dry eye (e.g., Stevens- Johnson 
syndrome, vitamin A deficiency, rheumatoid arthritis, Wegener’s 
granulomatosis, sarcoidosis, leukemia, Riley-Day syndrome, systemic 
lupus erythematosus, Sjogren’s syndrome). 
14. Use of any of the following medications: 
a) Systemic medication(s) that is known to cause ocular dryness 
(e.g., anti-histamines, diuretics, anti-hypertensives, anti-
depressants, hormone therapy) whose dose of this 
medication(s) has not been stable within 30 days prior to 
enrollment. There must be no anticipated adjustments to the 
dose of these medications for the duration of the trial. 
b) Oral tetracyclines or azithromycin within 30 days prior to 
enrollment; or 
c) Topical anti-glaucoma medications within 30 days prior to 
enrollment. 
d) Any other systemic medication as per to the Investigator’s 
discretion. 
15. Women in childbearing age who are pregnant, nursing, or not utilizing 
adequate birth control measures.  

Clinical Protocol Number: CLN 0858 Rev. 007 
18-Jan-2023 
Page 6 of 19 
 
16. Individuals using isotretinoin (Accutane) within 1 year, cyclosporine-
A (Restasis) or lifitegrast ophthalmic solution (Xiidra) within 45 days, 
or any other dry eye or MGD medications (antibiotics, non-steroidal 
anti-inflammatory drugs, corticosteroids) for at least 2 weeks; and to 
maintain abstinence throughout the duration of the study (ocular 
lubricants are allowed if no changes are made during the study). 
17.  Individuals wearing contact lenses 1 month prior the study (day 0) 
and at any point during the study. 
18. Current skin cancer, malignant sites and/or advanced premalignant 
lesions or moles in the treatment area. 
19. An impaired immune system condition or use of immunosuppressive 
medication. 
20. Collagen disorders, keloid formation and/or abnormal wound healing. 
21. Previous invasive/ablative procedures in the areas to be treated within 
3 months prior to initial treatment or plans for such treatment during 
the course treatment, or before complete healing of such treatments 
has occurred. 
22. Any patient who takes or has taken any oral or topical medications 
such as but not limited to topical retinoid (e.g., Retin-A), chemical 
peels, Latisse, Lash Boost which may cause fragile skin or impaired 
skin healing in the treatment area during the last 3 months and in the 
entire study period  
23. Any patient who has a history of bleeding coagulopathies. 
24. Any patient who has tattoos or permanent makeup in the treated area. 
25. Any patient who has burned, blistered, irritated or sensitive skin in any 
of the areas to be treated. 
26. Individuals using another ophthalmic investigational device or agent 
within 30 days of study participation. 
27. Any of the following dry eye treatments: 
a) Office-based dry eye treatment (e.g., IPL, LipiFlow, iLux, 
TearCare, Tixel, etc.) within 12 months prior to enrollment.  
b) Meibomian gland expression within 6 months prior to 
enrollment.  
c) Blephex or debridement within 3 months prior to enrollment 
is an exclusion. 

Clinical Protocol Number: CLN 0858 Rev. 007 
18-Jan-2023 
Page 7 of 19 
 
d) Punctal occlusion or punctal plug placement within 30 days 
prior to enrollment.  
e) Use of iTear or TrueTear device within the past 2 weeks. 
(Subjects must refrain from using these devices for the 
duration of the study.); or 
f) Any history of meibomian gland probing 
28. Use of at-home warm compresses or lid hygiene products while 
participating in study. 
29. IOP higher than 19 mmHg. 
30. Use of Botulinum-Toxin in the last 6 months prior to the treatment in 
the treatment area.  
31. Co-existing condition, either ocular or non-ocular that, in the 
judgement of the investigator could affect the safety or effectiveness 
of treatment or the compliance of the subject to the protocol. 
Schedule of 
Screening and 
Baseline 
Evaluations  
For Tixel and 
LipiFlow Groups 
 
Screening: (Must be done within 7 days prior to initial treatment (Day 0), but 
can be also done on the same day as baseline testing and initial treatment) 
• Informed Consent 
• Demographics/medical/ocular history 
• Concomitant systemic and ophthalmic medications  
• Patient’s report of the daily usage (frequency and dose) of eye 
lubricants  
• Determination of Fitzpatrick skin type 
Pre-
Treatment/Baseline 
Pre-Treatment/Baseline: (Must be done within 5 days prior to initial treatment 
but can be also done on the same day. All assessments must be done before 
randomization and performing either treatment)- the tests must be done in this 
order and by a masked investigator.  
• OSDI (administer first, self-assessed)  
• Refraction  
• Best Corrected distance visual acuity 
• Keratometry 
• Slit Lamp for Anterior Segment Health 
• Lid Margin Abnormalities 

Clinical Protocol Number: CLN 0858 Rev. 007 
18-Jan-2023 
Page 8 of 19 
 
• Eyelid Margin Assessment (including development of entropion or 
ectropion, floppy eyelids, lash integrity assessment) 
• TBUT  
• Corneal Fluorescein Staining Slit Lamp Evaluation 
• Conjunctival staining Lissamine green 
• Meibomian Gland Assessment and Scoring  
• Meibomian Gland expressibility test- At least 15 glands in each lower 
eyelid should be expressible, with a sterile cotton swab, at the slit 
lamp. 
• Intraocular pressure 
Randomization 
Randomization: (Performed after determining that the patient is eligible for 
the study) 
Patients will be randomized to the Tixel or control LipiFlow group in a 1:1 
ratio. Randomization will take place prior to patient treatment. The 
randomization allocation will be given to the patient directly from the EDC 
system. 
Schedule of Treatments – Tixel Group 
Treatment 1 
 
Tixel Group 
Treatment 1 (Day 0): Testing must be done in this order: 
• Patient’s report of the daily usage (frequency and dose) of eye 
lubricants. If data was collected at screening, only changes will be 
collected. 
• Tixel treatment on both eyes per instructions in Testing Methodologies 
for CLN 0858 study (CLN_0859) and IFU user manual 
The following assessments will be performed approximately 5 minutes after 
treatment: 
• Discomfort and Pain Questionnaires (self-assessed) 
• Slit Lamp for Anterior Segment Health  
• Corneal Fluorescein Staining Slit Lamp Evaluation 
• Conjunctival staining Lissamine green 
• Intraocular Pressure 

Clinical Protocol Number: CLN 0858 Rev. 007 
18-Jan-2023 
Page 9 of 19 
 
• Assessment for Adverse Events 
The post Treatment instructions sheet will be given to the patient following 
initial Tixel treatment. 
Schedule of phone 
call/video call/on-
site visit Follow-
Up Evaluation  
Post treatment 1 checkup call/video call (Day 2 +/- 1 day): 
The patient will be contacted, first by the study coordinator via phone, 1-3 
days post first treatment to check the patient condition. In case of any report 
of adverse reaction or skin reaction by the patient, the treating physician will 
contact the patient via video conference or on-site visit. The treating 
unmasked physician will perform the assessment as per  שגיאה! מקור ההפניה
.לא נמצא. 
Treatment 2 & 3 – 
Tixel Group Only 
Treatments 2 and 3: (Must be scheduled 2 weeks (+/-3 days) from the previous 
treatment). Testing must be done in this order: 
• Concomitant systemic and ophthalmic medications  
• Patient’s report of the daily usage (frequency and dose) of eye 
lubricants since the previous visit 
• Slit Lamp for Anterior Segment Health  
• Lid Margin Abnormalities 
• Eyelid Margin Assessment  
• Tixel treatment on both eyes per instructions in Testing 
Methodologies for CLN 0858 study (CLN_0859) and IFU user 
manual 
 
The following assessments will be performed approximately 5 minutes after 
treatment: 
• Discomfort and Pain Questionnaires (self-assessed) 
• Slit Lamp for Anterior Segment Health  
• Corneal Fluorescein Staining Slit Lamp Evaluation 
• Conjunctival staining Lissamine green 
• Intraocular Pressure 
• Assessment for Adverse Events 
Schedule of Treatments – LipiFlow Group 
LipiFlow Group 
Treatment 1 (Day 0): Testing must be done in this order: 

Clinical Protocol Number: CLN 0858 Rev. 007 
18-Jan-2023 
Page 10 of 19 
 
• Patient’s report of the daily usage (frequency and dose) of eye 
lubricants. If data was collected at screening, only changes will be 
collected 
• LipiFlow treatment on both eyes per instructions in Testing 
Methodologies for CLN 0858 study (CLN_0859) and IFU. 
The following assessments will be performed approximately 5 minutes after 
treatment: 
• Discomfort and Pain Questionnaires (self-assessed) 
• Slit Lamp for Anterior Segment Health  
• Corneal Fluorescein Staining Slit Lamp Evaluation 
• Conjunctival staining Lissamine green 
• Intraocular Pressure  
• Assessment for Adverse Events 
Schedule of phone 
call/video call/on-
site visit Follow-
Up Evaluation  
Post treatment 1 checkup call/video call (Day 2 +/- 1 day): 
The patient will be contacted, first by the study coordinator via phone, 1-3 
days post first treatment  to check the patient condition. In case of any report 
of adverse reaction or skin reaction by the patient, the treating physician will 
contact the patient via video conference or on-site visit. The treating 
unmasked physician will perform the assessment as per  שגיאה! מקור ההפניה
.לא נמצא. 
Follow Up Visits – Applicable for Tixel and LipiFlow Groups 
 
Follow-Up Visits: 4-Weeks (+/-7 days) and 12-Weeks (+/-14 days) after the 
last treatment: the tests must be done in this order and by a masked 
investigator 
 
• OSDI (administer first, self-assessed) 
• Concomitant systemic and ophthalmic medications 
• Patient’s report of the daily usage (frequency and dose) of eye 
lubricants since the last treatment 
• Refraction  
• Best Corrected distance visual acuity 
• Keratometry 
• Slit Lamp for Anterior Segment Health 
• Lid Margin Abnormalities 

Clinical Protocol Number: CLN 0858 Rev. 007 
18-Jan-2023 
Page 11 of 19 
 
• Eyelid Margin Assessment  
• TBUT  
• Corneal Fluorescein Staining Slit Lamp Evaluation 
• Conjunctival staining Lissamine green 
• Meibomian Gland Assessment and Scoring (MGS)  
• Intraocular Pressure  
• Assessment for Adverse Events 
 
Stage 2- Study Extension 
 
Study design:  
 
• Single arm observational study for long term follow-up after 
successful Tixel treatment based on the criteria below. 
• Only patients who completed their participation in the main study 
(stage 1) who meet the criteria are eligible to continue to the extension 
study. 
• Eligible patients who sign on an additional ICF for participation in 
stage 2 of the study will undergo a 6-months follow-up visit for 
effectiveness assessments.  
Note: Eligible subjects will be able to sign the informed consent form 
for stage 2 extension study, starting in the 3-months FU visit of the 
main study and up to the closure of the 6-months FU window. 
• Once a patient completed the 6-months FU visit he/she completed 
stage 2 of the study. 
Note: In the main study and the stage 2 extension study, we use both 3-months 
FU and 12-weeks FU interchangeably.   
Extension study 
endpoint:  
Durability of the clinical benefit effect which will be assessed at 6-months FU 
visit with the same parameters as in the main protocol (OSDI, TBUT and 
MGSS). 
Inclusion criteria:  
• Subjects who have completed the main study CLN 0858 (stage 1) in 
the Tixel arm. 
• TBUT -change from baseline in 1-month FU or 3-months FU was 2.5 
seconds or above at least in one eye in the main study. 
• Provision of written informed consent for stage 2. 
• Agreement/ability to abstain from dry eye/MGD medications for the 

Clinical Protocol Number: CLN 0858 Rev. 007 
18-Jan-2023 
Page 12 of 19 
 
time in the extension study. Ocular lubricants are allowed if no changes 
are made during the study. 
Exclusion 
criteria:  
Same as in the main study (stage 1).  
Schedule of 
evaluations: 
Screening and 6- months Follow-Up visit: 
Following completion of the 3-months FU visit in the main study, the 
investigator will discuss with potentially eligible subjects their continued 
participation in Stage 2 extension study. 
Following signing of informed consent for Stage 2 patients will be asked to 
return to the site 6 months (+/-30 days) after the last treatment for the 
following assessments (the tests must be done in this order) : 
All efforts will be done that assessments will be done by the same investigator 
who did the assessment in the 1-month FU and/or 3-months FU: 
• Informed consent for stage 2 
• Changes in concomitant systemic and ophthalmic medications since 
the last visit (3-month FU in the main study) 
• Patient’s report of the daily usage (frequency and dose) of eye 
lubricants (only if changes), since the last visit (3-month FU) in the 
main study. 
• OSDI (administer first, self-assessed) 
• Refraction  
• Best Corrected distance visual acuity 
• Keratometry 
• Slit Lamp for Anterior Segment Health 
• Lid Margin Abnormalities 
• Eyelid Margin Assessment  
• TBUT  
• Corneal Fluorescein Staining Slit Lamp Evaluation 
• Conjunctival staining Lissamine green 
• Meibomian Gland Assessment and Scoring (MGS)  
• Intraocular Pressure 
 
 

Clinical Protocol Number: CLN 0858 Rev. 007 
18-Jan-2023 
Page 13 of 19 
 
2. INTRODUCTION  
The aim of the current randomized, controlled study is to examine the effect of the Tixel device 
on the relief of the signs and symptoms of Meibomian Gland Dysfunction (MGD) compared to 
the FDA-cleared and CE approved device, LipiFlow. The design of this study is a non-
inferiority design which is the appropriate design considering the similarity of the mechanisms 
of the devices and the fact that treatments with LipiFlow commercially available in Europe and 
the United States for treating MGD. The purpose is to demonstrate that treatment with Tixel is 
also safe and effective for treating MGD.  
The funding for the study is done by the sponsor, Novoxel LTD. Details regarding the funding 
and the budget are specified in the clinical trial agreement with each site. 
2.1.Background  
Dry Eye Disease (DED) is often caused by a chronic lack of sufficient lubrication and moisture 
on the surface of the eye. Consequences of dry eyes range from subtle to constant eye irritation, 
significant inflammation and even scarring of the front surface of the eye. 
Meibomian glands are located in the tarsal plate of the upper and lower eyelids, where they 
terminate along the interior rim (or margin) of the eyelids. These glands secrete meibum, which 
is a lipid-rich essential component of a healthy tear film. When sufficient meibum is not present 
in the tear film, the aqueous layer of the tear film is disrupted and readily evaporates causing 
irritation, redness, and inflammation of the lid margin and surrounding tissues. Meibomian 
Gland Dysfunction (MGD) is associated with a failure of these glands to produce adequate 
quantities of meibum due to atrophy, inflammation, or obstruction and is thought to be the most 
common cause of evaporative Dry Eye Disease [1; Schaumberg DK 2011]. 
Initial treatments for the signs and symptoms related to MGD and DED are the use of oil-based 
artificial tears to supplement the lack of lipid in the tear layer and oral Omega and anti-
inflammatory prescriptions to decrease inflammation in the soft tissue in the eyelids. Another 
common treatment is the use of warm compresses applied over the eyelid for extended periods 
of time, followed by digital massage of the glands by the patient to try and express oil from the 
meibomian glands. The results of these treatments are often limited and temporary if not 
continued on a regular basis. 
 
 
 

Clinical Protocol Number: CLN 0858 Rev. 007 
18-Jan-2023 
Page 14 of 19 
 
2.2.Current alternative methods for treating dry eye 
Treatments to address this clinical need, aim to provide symptomatic relief, improve quality of 
life and correct underlying abnormalities of the ocular surface and tear film. The different 
treatment methods including medicinal (i.e., Lifitegrast), and medical devices such as: IPL, 
vector thermal pulsation (LipiFlow and i-Lux) and others1 ; Combination therapy, consisting of 
dry eye treatment (artificial tears, hyaluronic acid eye drops, Diquafosol ophthalmic solution) 
and lipid treatment, is effective in the improvement of both subjective and clinical symptoms. 
In case of microbial infection, MGD (Propionibacterium acnes [P. acnes] and Staphylococcus), 
antibiotic eye drops are used. Another common treatment is the use of a steroid antimicrobial 
ophthalmic solution. Treatment with Medical devices utilizing applied heat, such as hot 
compresses and mechanical pressure to achieve effects, such as:  
• Triggering the onset of meibum liquefaction, thus assisting in secretion through the gland 
orifices. 
• Melting of the oil blocking Meibomian glands. 
 Such devices include LipiFlow (Johnson & Johnson, New Brunswick, NJ), MeiboPatch (VISU 
pharma, Amsterdam, the Netherlands), Intense pulsed light (IPL) devices, etc. All of them treat 
DED and MGD. Several technologies have been studied by dermatologists and ophthalmologist 
regarding the ability of energy-based dermal devices to alleviate DED. Among them are IPL 
devices2 . According to Wang et al3, the complex multifactorial mechanisms of action of IPL 
therapy for MGD treatment is not fully understood. Both researchers have presented several 
possible IPL characteristics that may assist. It was proposed that delivery of thermal energy 
may assist in liquefaction of inspissated meibum and relieve ductal obstruction of the 
meibomian glands. Alternatively, antimicrobial effects of IPL therapy may dampen 
inflammatory triggers on the ocular surface. It was also suggested that the heat affects Demodex 
which influences DED. 
 
 
1 E. C. O’Neil, M. Henderson, M. Massaro-Giordano, V.Y. Bunya, Advances in dry eye disease treatment, Curr 
Opin Ophthalmol 2019, 30:166–178, DOI:10.1097/ICU.0000000000000569 
 
2 R. Aritaa, S. Fukuokab, N. Morishigec, Therapeutic efficacy of intense pulsed light in patients with refractory 
meibomian gland dysfunction, The Ocular Surface Volume 17, Issue 1, January 2019, Pages 104-110, 
https://doi.org/10.1016/j.jtos.2018.11.004 
 
3 M. T. M. Wang, U. Khatoon, Jennifer P. Craig, The use of intense pulsed light therapy in the treatment of 
refractory meibomian gland dysfunction, EXPERT REVIEW OF OPHTHALMOLOGY 2020, VOL. 15, NO. 4, 
197–200, https://doi.org/10.1080/17469899.2020.1752666 

Clinical Protocol Number: CLN 0858 Rev. 007 
18-Jan-2023 
Page 15 of 19 
 
2.3.Study Rationale  
Thermal pulsation has been used in clinical settings to provide heat and mechanical pressure to 
the eyelids to unblock plugged meibomian glands and reduce symptoms of MGD. Currently 
there are three FDA-cleared thermal pulsation devices; LipiFlow by Johnson and Johnson 
(K093937), iLux by Tear Film Innovations, Inc. (K172645), and TearCare by Sight Sciences 
(K213045). These systems apply heat (approximately between 40° to 45°C) on the eyelids 
(Lipiflow on the eyelid conjunctiva) and apply gentle pressure on the lid surfaces. Warming the 
eyelid tissue softens and/or melts the meibum, which is known to facilitate gland expression 
using pressure.  
The Tixel provides another thermal-based solution which has shorter exposure time, with lower 
thermal energy transfer, lower pressure, and no radiation emission whatsoever. Due to these 
suggested advantages Novoxel would like to further explore the performance of the device.  
Another research motivation has been discovered during research of treatment of periorbital 
wrinkles: The Tixel device has been used on the skin area around the eyes to reduce periorbital 
wrinkles. It has been reported by more than a 100 patients treated with the Tixel in some 
investigator-initiated studies that after treatment their eyes feel less dry. Further clinical 
information concerning these cases is depicted in the following section. 
2.4.Primary Efficacy Endpoint Rationale  
The primary objective of the study is to determine the effectiveness of the therapy in improving 
TBUT  in eyes with DED due to MGD. This objective was chosen because a reduced TBUT is 
one of the most common signs of DED due to MGD. TBUT is considered abnormal when 
shorter than 10 seconds.  
In this study we wish to compare the Tixel device to a marketed device, the LipiFlow system. 
In the comparative study of iLux vs LipiFlow the chosen NI margin was 2.5 seconds4. Since a 
criterion for clinically relevant improvement in TBUT has not been defined, clinical relevance 
was based on the labeling of the DET test strip which defines the difference between dry and 
normal tear stability as 5 seconds. Thus, a change of 2.5 seconds was defined as a clinically 
relevant change since it represents 50% of that defined in the DET strip labeling.  
 
 
4 Tauber J, Owen J, Bloomenstein M, Hovanesian J, Bullimore MA. Comparison of the iLUX and the LipiFlow 
for the Treatment of Meibomian Gland Dysfunction and Symptoms: A Randomized Clinical Trial. Clin 
Ophthalmol. 2020 Feb 12;14:405-418. 

Clinical Protocol Number: CLN 0858 Rev. 007 
18-Jan-2023 
Page 16 of 19 
 
3. STATISTICAL CONSIDERATIONS  
3.1.General Considerations  
Descriptive statistics will be used to summarize continuous variables (number of eyes/patients 
[N], mean, standard deviation (SD) or standard error of the mean, median, maximum, and 
minimum) and categorical variables (frequency and percentage) at each assessment timepoint. 
Statistical comparisons within each group will be performed using appropriate statistical 
methods or models, and the results such as 95% confidence intervals and p values will be 
reported. All summary tables will be supported with individual patient and eye data listings. 
Baseline is defined as the last non-missing observation prior to initiation of study intervention. 
Analyses will be carried out using SAS software or equivalent statistical software. 
Further details will be described in the statistical analysis plan, which will be finalized prior to 
the study database lock. 
3.2.Analysis Populations 
• 
Intent-to-Treat Population: The intent-to-treat (ITT) population includes all randomized 
patients. Patients will be analyzed as randomized.  
• 
Per Protocol Population: The per protocol (PP) population includes all patients who 
performed the 4 weeks follow-up visit, completed all the treatments as randomized, and 
have no major protocol deviations. Patients will be analyzed as treated. The primary 
analysis population will be the per-protocol (PP) population. 
• 
Safety Population: The safety population will include all treated patients. The safety 
population will be analyzed for all safety assessments. Patients will be analyzed as 
treated. A summary table of number (%) of patients in each analysis population/set will 
be provided. 
3.3.Demographic and Baseline Characteristics 
Descriptive statistics or frequency tabulation will be provided for demographic and baseline 
characteristics, such as age, gender, race, and ethnicity. 
3.4.Effectiveness Analyses  
3.4.1. Primary effectiveness endpoint 
- 
The primary endpoint of change from baseline in the TBUT as rated by a masked rater 
at 4 weeks will be analyzed for non-inferiority using a margin of 2.5 seconds.  
The primary non-inferiority hypothesis set will be: 

Clinical Protocol Number: CLN 0858 Rev. 007 
18-Jan-2023 
Page 17 of 19 
 
Ho: µTixel - µLipiflow + δ ≤ 0 
HA: µTixel - µLipiflow + δ > 0 
where µTixel and µLipiflow are the mean TBUT changes from baseline at 4 weeks for 
Tixel and Lipiflow, respectively and δ=2.5. 
A change in TBUT of at least 2.5 seconds in each group will be considered clinically 
significant. 
The difference between Tixel and Lipiflow in changes from baseline in TBUT as rated 
by a masked rater at 4 weeks will be assessed using a linear mixed-effects model with 
a random effect for subjects and fixed effect for treatment and baseline score as 
covariate. The random-effect adjusts the “within-subject correlation” between eyes. 
Least square means will be estimated by treatment arm from the model. The confidence 
interval for the estimates will be one-sided and a test value of 2.5 will be used to test 
non-inferiority. 
 
3.4.2. Secondary effectiveness endpoints 
1- OSDI 
- 
The change from baseline at 4 weeks and 12-weeks in the Ocular Surface Disease Index 
(OSDI) will be calculated along with 95% confidence interval. The Paired T-test or 
Signed rank test for two means (paired observations) (as is appropriate) will be applied 
for testing the statistical significance of the changes within each study group. 
- 
The two-sample T-test or Non-parametric Wilcoxon-Mann-Whitney Rank sum test for 
independent samples (as is appropriate) will be applied for testing the statistical 
significance of the difference in change from baseline in OSDI at week 4 between the 
study groups 
2- MGS  
- 
The difference between Tixel and Lipiflow in changes from baseline in MGS as rated 
by a masked rater at 4 weeks and 12 weeks will be assessed using a linear mixed-effects 
model with a random effect for subjects and fixed effect for treatment and baseline score 
as covariate. The random-effect adjusts the “within-subject correlation” between eyes. 
Least square means will be estimated by treatment arm from the model. 
 
3- TBUT 

Clinical Protocol Number: CLN 0858 Rev. 007 
18-Jan-2023 
Page 18 of 19 
 
- 
 In 12 weeks, the follow-up visit will be analyzed in the same way as the 4-weeks 
follow-up visit.  
 
3.4.3. Exploratory Analysis: 
- 
For each follow-up (4 weeks and 12 weeks), if non-inferiority is achieved, the TBUT 
score change from baseline as rated by a masked rater at the relevant follow will be 
analyzed for superiority. The hypothesis set will be: 
- 
Ho: µTixel - µLipiflow ≤ 0 
- 
HA: µTixel - µLipiflow > 0 
3.5.Handling of Missing data 
Every effort will be made to complete follow-up for all patients and avoid missing data, in 
particular regarding the primary endpoint variable. However, in the event data is missing, 
multiple imputation will be used. Further details will be provided in the statistical analysis plan. 
3.6.Interim Analysis 
No interim analyses are planned for this study. 
3.7.Sample Size Justification 
55 patients will be enrolled in each treatment group. 
Sample size rationale: 
The sample size calculation is based on the primary efficacy endpoint. Specifically, the sample 
size calculation was based on the non-inferiority with a 2.5 second margin of the change from 
baseline in TBUT score as assessed by a masked rater at 4 weeks follow-up for Tixel versus 
LipiFlow. The expected standard deviation of the difference in change is 4.5 seconds.  
The calculation assumes the worst-case scenario that the TBUT of both subjects eyes subjects 
is completely correlated (r=1).   
Sample size justification: 
When the sample size in each group is 44, a two group one-sided 0.05 significance level t-test 
will have 80% power to reject the null hypothesis that the test and standard are not non-inferior 
(the difference in means, μT-μL, is 2.5 seconds or farther from zero in the same direction) in 
favor of the alternative hypothesis that the means of the two groups are non-inferior, assuming 
that the expected difference in means is 0 and the common standard deviation is 4.5 s. 

Clinical Protocol Number: CLN 0858 Rev. 007 
18-Jan-2023 
Page 19 of 19 
 
Assuming a 20% drop-out rate, 55 patients will be enrolled in each group ensuring a sample 
size of 44 patients per group. 
[4 -Dixon et al, 1983; 5 O'Brien et al, 1993] 
3.8.Poolability Analysis  
Patient demographic characteristics and background variables shall be summarized.  
The primary endpoint analysis will be conducted for each investigational site. The justification 
for pooling all the data to estimate a common effect across study sites requires the homogeneity 
of response across study sites. An analysis of variance (ANOVA) of the differences will be 
generated to test whether the investigational sites differ with respect to primary study endpoint 
(only the site will be included in this analysis model). The test of inhomogeneity of response 
will be based on a two-sided significance test at the 0.15 level of significance. If the sites differ 
by this test, then a second analysis will be done including study site and all baseline 
characteristics that have P<0.10 in the analysis of baseline characteristics by site to understand 
if the imbalance in the primary endpoint between sites is related to an imbalance in baseline 
characteristics.