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

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A RANDOMIZED, MASKED (EVALUATOR), CONTROLLED, 
PROSPECTIVE PILOT STUDY OF THE EFFECTIVENESS 
AND SAFETY OF THE TIXEL®, VERSUS LIPIFLOW® IN THE 
TREATMENT OF MEIBOMIAN GLAND DYSFUNCTION  
 
Study Protocol No:  
CLN 0798 
 
Version: 
 
 
2.0 
 
Version Date: 
 
June 21, 2021 
 
Investigational Product: 
Tixel Fractional System  
 
Sponsor: 
                  Novoxel Ltd. 
 
 
 
 
43 Hamelaha St. 
 
 
 
 
 
Contacts:  
 
 
Ifat Klein, PhD  
VP of Clinical Affairs 
ifat@novoxel.com 
Raphi Shavit 
Chairman, Novoxel Ltd. 
Raphi@novoxel.com 
 
 
 
 
 
 
 

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תןכו 
 
INTRODUCTION 4 
1.1 
Background 4 
1.2 
Study Rationale 
4 
1.3 
Primary efficacy endpoint rationale 
5 
 
The investigational device 
6 
2.1 
Device description 6 
2.2 
Safety Features of the Tixel C  7 
 
Lipiflow® system 
9 
3.1 
LipiFlow Indications for Use 
9 
3.2 
LipiFlow Components 
9 
 
CLINICAL STUDY DESIGN 10 
4.1 
Objective 
10 
4.2 
Description of the Study 
10 
4.2.1 
Primary Effectiveness Endpoint 
10 
4.2.2 
Secondary Effectiveness Endpoints 
10 
4.2.3 
Primary Safety Endpoint 
11 
4.2.4 
Secondary Safety Endpoints 
11 
 
PATIENT POPULATION 
12 
5.1 
Inclusion Criteria 
12 
5.2 
Exclusion Criteria 12 
 
STUDY PROCEDURES 
14 
6.1 
Patient Screening and Enrolment 14 
6.1.1 
Informed Consent 
14 
6.1.2 
Patient Identification 
15 
8.1.3   General Examination 
15 
8.1.4    Fitzpatrick Skin Type 
15 
6.2 
Pre-Treatment/Baseline Assessments 
16 

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6.3 
Randomization 
19 
6.4 
Schedule for Study Visits 20 
6.5 
Treatments 20 
6.6 
4-Weeks Follow-Up Visit 23 
6.7 
12-Weeks Follow-Up Visit 23 
 
Statistical Considerations 
24 
7.1 
General Considerations 
24 
7.2 
Analysis Populations 
24 
7.3 
Demographic and Baseline Characteristics 
25 
7.4 
Effectiveness Analyses 
25 
7.5 
Handling of Missing data 26 
7.6 
Interim Analysis 
26 
7.7 
Sample Size Justification 26 
7.8 
Poolability Analysis 
26 
7.9 
Safety Analyses 
27 
 
 
 

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 INTRODUCTION  
1.1 
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. 
1.2 
Study Rationale  
Thermal pulsation has been used in clinical settings to provide heat and mechanical stimulation 
to the eyelids to unblock plugged meibomian glands and reduce symptoms of MGD. Currently 
there are two FDA cleared thermal pulsation devices; LipiFlow by Johnson and Johnson 
(K112704) and iLux by Tear Film Innovations, Inc. (K172645). The LipiFlow and iLux 
systems place a heated plate (40 to 43°C) against the eyelids (Lipiflow on the eyelid 
conjunctiva) and apply gentle pressure on the lid surfaces. Warming the eyelid tissue softens or 
melts the meibum, which is known to facilitate gland expression using pressure.  
The Tixel device uses heat delivered by a small hot element called the Tip. The device tip is 
heated during treatment and contacts the skin for a very short period each time it is applied. The 
Tixel device has been used on the skin area around the eyes to reduce wrinkles, but it has been 
reported by patients treated with the Tixel that after treatment their eyes feel less dry. The Tixel 

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system, although applying higher temperature compared with the two predicate devices, is 
considered to mimic the combination of pressure and temperature effect in a similar manner.  
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 approved device, LipiFlow. 
1.3 
Primary efficacy endpoint rationale  
The primary objective of the study is to determine the efficiency 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. The reason for choosing the margin of 1.5 second as a success criterion 
is following the recent IPL study performed by Lumenis and received an FDA approval. In the 
study the difference between the IPL arm and the control arm was 1.24 second. The IPL arm 
was 1.99 second in combination with MGX, and the sham +MGX was 0.75 meaning that the 
IPL alone was responsible to 1.24 second from baseline to 4 weeks follow-up (Effectiveness of 
Intense Pulsed Light for Improving Dry Eye Syndrome - Study Results - ClinicalTrials.gov). 
 
 

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 THE INVESTIGATIONAL DEVICE 
2.1 
Device description 
Tixel C )Novoxel®, Israel) is a thermomechanical system developed for fractional treatment. 
The system is designed for the treatment of soft tissue by direct conduction of heat, enabling 
tissue coagulation combined with micro ablation with low thermal damage to the surrounding 
tissue.  
 
The system consists of a handpiece connected to a console (Figure 1).  The handpiece applies 
a therapeutic element, the "tip", fixated on the distal section. The tip is comprised of a gold-
plated copper base and a thin-walled titanium alloy cover (Figure 2) 
 
 
 
 
 
               Figure 1 - The Tixel C Console and Handpiece Configuration 
Figure 2 - The Tixel Small Tip 

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The handpiece is equipped with a precise motion system based on a linear motor and a digital 
signal processing (DSP) motion controller. The system design enables precise pre-set periods 
of skin contact duration. The active surface of the Tixel small Tip consists of an array of 24 
(6x4) square-based pyramids evenly spaced within a boundary area of 0.30cm2. The pyramids 
are 1.25mm tall with a flat rectangular apex of approximately 0.01mm2. The blunt apex of the 
pyramid allows effective heat transfer and prevents mechanical puncturing of the skin. The 
backplane of the tip attaches to a ceramic heater that maintains a Tip base temperature of 400°C 
during the treatment. The heating enables effective self-sterilization before and during 
treatment, significantly reducing the risk of cross-contamination from the tip. When the 
handpiece is not activated, the tip is safely retracted to its home position. When the user 
activates the handpiece, the linear motor rapidly advances the tip which comes in brief contact 
with the tissue, and then pulls it back. Thermal energy is transferred to the skin, creating tissue 
micro ablation and tissue coagulation. The tip recedes within a precisely controlled distance 
and time to its home position. The duration of the pulse, defined as the time of contact between 
tip and skin, ranges from 5ms to 16ms.  
A second system parameter is the travel or “protrusion” of the tip. Protrusion is defined as the 
distance that the tip travels from the distal edge of the handpiece (which also functions as a 
distance gauge). The protrusion adjustment, measured in micrometres (µm), is designed to 
ensure good thermal coupling between the tip and the tissue. Adequate combined settings of 
the two parameters, pulse duration and protrusion, contribute to the desired thermal effect 
followed by the clinical outcome. 
2.2 
Safety Features of the Tixel C 
-The device tip base temperature is maintained at 400°C, but the dermal thermal lesion under 
the specified operation parameters is limited to 250µm (for eyelid treatment parameters), while 
eyelid thickness varies between 500-1500 µm. Therefore, there is no risk related to the Tip 
temperature to the eyelid muscles or meibomian gland or to the eye (sclera or cornea) as shown 
in pre-clinical and human body histology.  
-When the device is contacting the skin for extremely short periods of time, the maximal tissue 
temperature creating micro ablation is lower than 150°C. The pressure applied by the tip during 
contact is limited to gently “compress” the eyelid surface resulting in negligible pressure on the 
eye as shown in laboratory tests. 

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-The device is IEC-60601 certified (both safety and EMC tests). 
-Tixel is approved for use as a medical device by the FDA (The previous version of the Tixel 
C equipped with the same handpiece and Tip assembly) European Union, Australia, Brazil, 
South Africa, South Korea, Taiwan Thailand, Israel, among other countries.  
-Two clinical studies of the Tixel treatment of peri-orbital wrinkles have received IRB 
approvals (3 clinical sites in the US and 3 clinical sites in Israel). One study was completed 
without any related AEs and only 2 patients with AEs in total (5.9%) in the Tixel group. A 
second study is under process.  
-The Tixel device is designed with core safety, which is ensured via several aspects of its 
components: 
 
-The device has an over-temperature automatic thermal shutdown in case of 
        undesired temperature rise. This component is strictly hardware based.  
 
-In case of a power fail, the tip will always be retracted backwards to its home  
                   position. 
 
-The system is always in a rested (home) position and activated only when the 
                   trigger is pressed.  
 
-An air-cooled system which does not contain any type of cooling liquid such as 
                   water. 
 
-Mechanical BIT (Built-In Test).  Before commencing operational mode, the system  
                   verifies free motion of the mechanical system.  
 
 

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 LIPIFLOW® SYSTEM 
The LipiFlow System is a medical device intended for use by Eye Care Professionals (ECP) to 
apply localized heat and pressure therapy to a patient’s eyelids. It is cleared to be marketed by 
the United States Food and Drug Administration and will be used as the control device in this 
study.  
 
3.1 
LipiFlow Indications for Use  
The LipiFlow System is indicated for the application of localized heat and pressure therapy in 
adult patients with chronic cystic conditions of the eyelids, including meibomian gland 
dysfunction (MGD), also known as evaporative dry eye.  
3.2 
LipiFlow Components  
The LipiFlow Console provides the user interface and control elements of the system, including 
software, algorithms and control elements (Figure 3).  
 
 
 
 
Figure 3 - The LipiFlow Console and Activator disposable 
 
The Activator, a single-use sterile device, delivers automated therapeutic energies to each 
meibomian gland. Its contoured design vaults the cornea and protects the eye allowing a 
maximum therapeutic temperature of 43 degrees Celsius to reach glands from the inner eyelid, 
without damaging the eyelid or delicate structures of the globe. Insulation protects the cornea 
from exceeding a safe 39.5 degrees Celsius, while a pressure feedback loop sends pulsed 

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sequences to expel blockages. Force equalization protects the globe from pressure transmission 
by focusing energy only on the eyelid. Delivered through the LipiFlow Activator, Vectored 
Thermal Pulse™ (VTP) technology applies a combination of heat and pressure to the inner 
eyelid to safely remove gland obstructions and stagnant gland content. Vectored heat and 
adaptive force equalization targets the pulse, heat, and pressure on the meibomian glands to 
maximize effectiveness. Therapeutic motion provides proximal-to-distal parastalsis to clear 
gland contents. 
 
 
 CLINICAL STUDY DESIGN  
4.1 
 Objective  
The objective of this study is to evaluate the safety and effectiveness of the Tixel device in 
adults with meibomian gland dysfunction (MGD).  
4.2 
Description of the Study  
This study is a randomized, open-label, pilot clinical study comparing the Tixel device to an 
active control, which will be the LipiFlow System. The goal of this study is to compare between 
the Tixel device and the LipiFlow System and estimate the magnitude of the differences, if they 
exist, in terms of safety and effectiveness. A total of up to 30 patients (60 eyes) will be 
randomized for bilateral treatment and will be assigned in a 1:1 ratio into the Tixel treatment 
group or the control group at up to 2 study sites in Israel and/or Europe. The evaluator 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. One eye will be 
selected as the designated “study eye” for statistical purposes: The study eye is the eye with the 
lower baseline TBUT. If both eyes have the same TBUT, the right eye will be the study eye. 
Outcome Measures 
4.2.1 Primary Effectiveness Endpoint  
The primary effectiveness endpoint is the change from baseline to the 4-weeks follow up exam 
in Tear Break-Up Time (TBUT).  TBUT must be assessed by a masked rater. The changes from 
baseline will be evaluated.  
4.2.2 Secondary Effectiveness Endpoints  

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• Change from baseline in patient symptoms using the Ocular Surface Disease Index 
(OSDI) at the 4-weeks and 12 weeks follow-up exam. OSDI is a scoring that evaluates 
patient symptoms based on a validated questionnaire [4]. 
• Changes from baseline to 4-weeks and the 12-weeks follow-up exam in Meibomian 
Gland Score (MGS). MGS must be assessed by a masked rater. 
The MGS is determined for the lower eyelids using a device that applies a standardized 
pressure to an area including 5 glands (Meibomian Gland Evaluator, Johnson & Johnson 
Vision) while viewing the eyelid margin using a slit lamp microscope to determine the 
presence and quality of the gland secretions.  A total of 15 glands in three lower eyelid 
zones (nasal, medial, temporal) will be evaluated.  Each gland is graded from 0 to 3 (0 
= no secretion, 1 = inspissated, 2 = cloudy, 3 = clear liquid). The maximum MGS score 
is 45 in each eye. The clinician performing the MGS must not be involved in the study 
procedure and must be blinded to which arm of the study the patient is randomized. 
• Change from baseline to the 12-weeks follow-up exam in Tear Break Up Times 
(TBUT), as assessed by a masked rater. 
4.2.3  Primary Safety Endpoint  
The primary safety endpoint will be a comparison of the incidence of device-related adverse 
events (e.g., increase in the lid margin such as development of floppy eyelids, entropion or 
ectropion; and lash integrity) for the two-treatment arms.  
4.2.4 Secondary Safety Endpoints  
Secondary safety endpoints will be the following assessments: 
 • The evaluation of discomfort and pain during treatment 
 • Changes from baseline following treatment for the test and control devices for the   
    following assessments: 
    o Ocular Surface Staining  
    o Intraocular Pressure 
    o Cornea OCT evaluation to detect changes (cornea thickness, cornea deamination) 
       following treatment- will be performed on a subset of 10 patients, who first  
       enrolled, only in the Tixel arm (since LP has a protective cup on the cornea). 
 
 

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 PATIENT POPULATION  
The study will include adult patients with symptoms of MGD/evaporative dry eye. 
5.1 
 Inclusion Criteria 
1. Age 18 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. A positive history of self-reported dry eye symptoms for three months prior to the study 
using the Ocular Surface Disease Index (OSDI) questionnaire, and a score of ≥ 23 at the 
baseline visit. 
5. Evidence of meibomian gland (MG) obstruction, based on a total Meibomian Gland 
Score (MGS) of ≤12 in the lower eyelids for each eye. The rater of MGS must not be 
involved in the study procedure. 
6. Non-invasive tear break-up time (TBUT) <10 seconds in both eyes. The rater of TBUT 
must not be involved in the study procedure. 
7. Agreement/ability to abstain from dry eye/MGD medications for the time between the 
treatment visit and the final study visit. Ocular lubricants are allowed if no changes are 
made during the study. 
8. Fitzpatrick skin type I-VI. 
5.2 
Exclusion Criteria  
1. History of ocular surgery including intraocular, oculo-plastic, corneal or refractive 
surgery within 1 year. 
2. Patient with giant papillary conjunctivitis. 
3. Patient 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 within the 
last 3 months. 
6. Patient who are aphakic. 
7. Cicatricial lid margin disease identified via slit lamp examination, including 
pemphigoid, symblepharon, etc. 
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). 

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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 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. Unwillingness to abstain from systemic medications known to cause dryness for the 
study duration. 
15. Women in child baring age who are pregnant, nursing, or not utilizing adequate birth 
control measures.  
16. Individuals who have either changed the dosing of systemic or non-dry eye/MGD 
ophthalmic medication within the past 30 days prior to screening. 
17. Individuals who are unable or unwilling to remain on a stable dosing regimen for the 
duration of the study. 
18. Individuals using isotretinoin (Accutane) within 1 year, cyclosporine-A (Restasis) or 
lifitegrast ophthalmic solution (Xiidra) within 3 months, 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). 
19.  Individuals wearing contact lenses at any time during the prior three months and at any 
point during the study. 
20. Current skin cancer, malignant sites and/or advanced premalignant lesions or moles in 
the treatment area. 
21. An impaired immune system condition or use of immunosuppressive medication. 
22. Collagen disorders, keloid formation and/or abnormal wound healing. 
23. 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. 

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24. Any patient who takes or has taken any oral or topical medications, herbal treatments, 
food supplements, or vitamins which may cause fragile skin or impaired skin healing 
during the last 3 months. 
25. Any patient who has a history of bleeding coagulopathies. 
26. Any patient who has tattoos or permanent makeup in the treated area. 
27. Any patient who has burned, blistered, irritated, or sensitive skin in any of the areas to 
be treated. 
28. Individuals using another ophthalmic investigational device or agent within 30 days of 
study participation. 
29. Individuals that were treated with LipiFlow in the last 24 months, or Tixel at any point 
in the past. 
30. Treatment in either eye with IPL in the last year. 
31. Expression of the meibomian glands within 6 months prior to screening. 
32. Use of at home warm compresses or lid hygiene products while participating in study. 
 
 STUDY PROCEDURES 
6.1 
 Patient Screening and Enrolment  
Patients will be screened, assessed, treated and followed according to the schedule of events in 
Appendix A. Patients must have the study explained to them by the Investigator/Sub-
investigator (or other delegated study team if allowed by local regulations), they must be 
provided sufficient time to consider their participation in the study and provided an opportunity 
to ask questions of the study team.  Patients must sign the most current version of an informed 
consent form (ICF) approved by an Institutional Review Board (IRB)/Ethics committee. All 
patients who sign an ICF and meet the entire protocol criteria are considered enrolled patients 
in the study; if not, they will be considered as screen-failures. Therefore, patients should be pre-
screened to the extent possible prior to signing an ICF, but patients should not undergo any 
study-specific assessments until they have signed the ICF.  
6.1.1 Informed Consent 
During the informed consent (IC) process with the patient, the study investigator or designee 
will explain the purpose of the study, the possible risks and benefits, and the schedule of visits 
required for participation. The study investigator or designee will explain to the patient that, 

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after signing the IC form, the patient may not be found eligible to participate in the study if 
he/she doesn’t  meet all inclusion/exclusion criteria. 
The patient may take the IC form and consult with their family, friends or doctor. After reading 
and understanding the IC, if the patient decides that he/she wishes to participate in the study, 
he/she should return, with a signed IC form at which time he/she will undergo specific tests as 
specified in Appendix A. These tests will be done only after the patient signed the ICF, clearly 
indicating his/her understanding of the requirements and risks involved with study participation 
and other applicable treatment options. 
6.1.2 Patient Identification 
At the screening, the patient will receive a unique identifying Patient ID number that will be 
composed of the site number (2 digits) and a three-digit consecutive patient number. This 
unique Patient ID will be used throughout the entire study and will be entered in the patient's 
eCRFs for the screening visit, baseline visit, each treatment visit and the follow-up visits. 
8.1.3   General Examination  
A general clinical examination is required to assess eligibility. This examination will include 
demographics information, past medical and ocular history, known allergies, use of 
Concomitant Systemic and Ophthalmic Medications and patient’s report of the daily usage 
(frequency and dose) of eye lubricants. 
     8.1.4    Fitzpatrick Skin Type 
The Fitzpatrick skin type will be determined according to genetic disposition, reaction to sun 
exposure and tanning habits. The Fitzpatrick scale classifies 6 skin types, as summarized below. 
In this study, all Fitzpatrick skin types I-VI are eligible to participate, consistent with the device 
labelling. 
TYPE I: Highly sensitive, always burns, never tans. Example: Red hair with freckles 
TYPE II: Very sun sensitive, burns easily, tans minimally. Example: Fair skinned, fair haired 
Caucasians 
TYPE III: Sun sensitive skin, sometimes burns, slowly tans to light brown. Example: Darker 
Caucasians. 
TYPE IV: Minimally sun sensitive, burns minimally, always tans to moderate brown. Example: 
Mediterranean type Caucasians, some Hispanics. 
TYPE V: Sun insensitive skin, rarely burns, tans well. Example: Some Hispanics, some Blacks 

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TYPE VI: Sun insensitive, never burns, deeply pigmented. Example: Darker Blacks. 
6.2 
Pre-Treatment/Baseline Assessments  
The following assessments will be performed at the baseline visit, for both treatment arms, prior 
to treatment (Note: The OSDI must be administered self-assessed prior to clinical evaluations). 
The detailed instructions can be found in the Testing Methodologies for CLN 0798 study 
(CLN_0802). 
Table 1-Patient Assessments  
Assessment  
Description 
OSDI 
Scoring that evaluates patient symptoms based on a validated 
questionnaire [2 Schiffman RM, 2000].  (OSDI Questionnaire 
provided in Appendix B).  OSDI questionnaires include 12 
questions in 3 categories. The questionnaire is self- assessed 
where patients are asked to circle a number next to a 
description that best represents their answer on a paper form. 
The numbers for each category are totalled and the total OSDI 
score is calculated by the formula: sum of scores x 25/# of 
questions answered.  Dry eye severity is then assessed using 
the chart on the 2nd page of the questionnaire. 
Uncorrected Distance 
Visual Acuity 
Patient will be seated with no glasses in front of a Snellen 
vision chart that is calibrated to measure at 6 meters. 
Corrected Distance Visual 
Acuity 
If patient does not regularly wear glasses for distance this test 
will not be done.  
The patient will be seated with glasses (if worn) in front of a 
Snellen vision chart that is calibrated to measure at 6 meters.  
Keratometry 
Test of corneal curvature conducted using a manual 
keratometer 
or 
simulated 
keratometry 
from 
corneal 
topography. 
Slit Lamp for Anterior 
Segment Health 
Using biomicroscopy to examine anterior segment including 
lids, adnexa, conjunctiva, sclera, corneal clarity, and surface 
integrity, anterior chamber, and iris. Grading system: 

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• 0=No clinical findings 
 • 1=Non-clinically significant positive findings (including 
pterygium, pinguecula, corneal scar, conjunctival pigment, 
corneal arcus, verucca, non-visual significant lens changes) 
 • 2=Abnormal findings 
Lid Margin Abnormalities 
Scored 0-4 based on the number of the following present in 
each eye:  
• irregular lid margin 
 • vascular engorgement 
 • plugged meibomian gland orifices 
 • anterior or posterior replacement of the mucocutaneous 
junction 
Eyelid Margin Assessment 
Development of any of the following:  • entropion or ectropion 
• floppy eyelids • loss of lash integrity 
Tear Break-Up Time 
(TBUT) 
Note: TBUT Assessments must be made by a rater not 
involved in the study procedure and blinded to the arm to 
which the patient is randomized 
• 
Use one Fluorescein strip per eye 
• 
Apply one or two drops of non-preserved saline to 
the impregnated paper tip. Excess fluid will 
automatically fall off. Shaking is neither required nor 
desirable 
• 
Ask the patient to look down and in 
• 
Gently touch the strip to the superior temporal bulbar 
conjunctiva for one or two seconds 
• 
Ask the patient to blink three times and open eyes 
naturally 
• 
Immediately measure the time between the last blink 
and the first appearance of a dark spot on the cornea 
(formation of dry area) 
• 
Time shall be recorded in seconds and shall be the 
average of three consecutive measurements 
• 
Repeat with a new strip for the second eye 

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Corneal Fluorescein 
Staining Slit Lamp 
Evaluation 
• 
Use one Fluorescein strip per eye. 
• 
Apply 1-2 drops of non-preserved saline to the 
impregnated paper tip. Excess fluid will 
automatically fall off. Shaking is neither required nor   
Desirable. 
• 
Ask the patient to look down and in. 
• 
Gently touch the strip to the superior temporal bulbar 
conjunctiva for one or two seconds. 
• 
Start with low illumination and gradually increase 
until staining is visible. 
• 
Grade each region according to the National Eye 
Institute corneal grading below and record the Total 
Score for each eye. Score will range from 0 to 15. 
 
National Eye Institute (NEI) corneal grading scale evaluating 
five corneal regions:  
 • superior 
 • inferior  
 • central  
 • temporal  
 • nasal 
Each graded on a 0-3 scale (0=normal-no staining; 1=mild-
superficial stippling micropunctate staining; 2=moderate-
macropunctate staining with some coalescent areas; 3=severe-
numerous coalescent macropunctate areas and/or patches) [3 
Lemp MA.1995] 
Conjunctival staining 
Lissamine green 
• 
Use one Lissamine green strip per eye. 
• 
Apply 1-2 drops of non-preserved saline to the 
impregnated paper tip. Excess fluid will 
automatically fall off. Shaking is neither required nor 
desirable. 
• 
Ask the patient to look down and in. 
• 
Gently touch the strip to the superior temporal bulbar 
conjunctiva for one or two seconds. 
• 
Wait at least 1 minute before grading the 
conjunctival staining.  Perform grading within 4 
minutes of instilling the dye. 
• 
Start with low illumination and gradually increase 

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until staining is visible. 
• 
Record the grade (0-3) of each of the regions (nasal, 
superior nasal, inferior nasal, temporal, superior 
temporal, inferior temporal) and record the Total 
Score for each eye. Score will range from 0 to 18. 
(0=normal-no staining; 1=mild-superficial stippling 
micropunctate staining; 2=moderate-macropunctate 
staining with some coalescent areas; 3=severe-
numerous coalescent macropunctate areas and/or 
patches). 
• 
Make sure to identify pooling or a stained mucus 
strand. Ask patients to blink a couple of times when 
in doubt. 
Meibomian Gland 
Assessment and Scoring  
Note: Meibomian Gland Assessments must be made by a rater 
not involved in the study procedure and blinded to the arm to 
which the patient is randomized. 
 • Assess lower eyelids using Meibomian Gland Evaluator 
while viewing the eyelid margin using slit lamp microscope 
 • Evaluate 15 glands in 3 zones (nasal, medial, temporal) 
 • Each gland graded from 0 to 3 
 • Maximum MGS score=45 in each eye  
[4 Lane SS. 2012, 5 Blackie CA. 2015]  
Intraocular Pressure 
Measured by a Goldmann tonometer and recorded in mmHg 
Optical Coherence 
Tomography (OCT) 
(Will be done only after 
randomization)  
 
 
OCT assessment should be performed before any corneal 
testing. Cornea OCT evaluation will be done to detect 
changes (cornea thickness, cornea deamination) between 
baseline and following treatments- will be performed after 
randomization, on a subset of 10 patients (the first 10 
enrolled patients), only in the Tixel arm. Images will be 
coded with site number, patient screening number, visit 
number and left/right eye and will be uploaded to EDC 
and/or SharePoint. 
6.3 
Randomization  

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Prior to randomization it must be determined that the patient meets all entrance criteria.  This 
includes the completion of all screening tests to determine eligibility.   The randomization 
schedules with patients allocated to the Tixel or control LipiFlow group in a 1:1 ratio will be 
prepared for each site. Each envelope will have a sequential envelope number on the outside 
and contain the assigned treatment procedure inside. Before the treatment, the assigned 
personnel will open the lowest numbered envelope. The envelope number will be documented 
on the study source documents and in the EDC.  Randomization will take place at the treatment 
visit prior to patient treatment.  There are no criteria for crossover in this study, so all patients 
must be treated according to the arm to which they are randomized. 
6.4 
Schedule for Study Visits  
For the Tixel: 
After the randomization to the Tixel arm, each patient will undergo 3 treatment sessions  
(Day 0, Week 2, Week 4) at 2 weeks intervals (+/-3 days) from the previous treatment, and 
follow-up sessions at 4-weeks (+/-7 days) and 12-weeks (+/-14 days) after the last treatment 
session.  
For the LipiFlow: 
After the randomization to the LipiFlow arm each patient will undergo 1 treatment session 
(Day 0), and follow-up sessions at 4-weeks (+/-7 days) and 12-weeks (+/- 14 days) after the 
treatment session.  
6.5 
Treatments  
The study procedure in both study arms shall be performed on both eyes on the same day. 
Testing must be done in the following order:  
• Concomitant systemic and ophthalmic medications (before treatment 1, only if not done 
during screening). 
• Patient's report of the daily usage (frequency and dose) of eye lubricants. Before 
treatment 1, only if not done during screening. If data was collected at screening, only 
changes will be collected. 
Before treatments 2 and 3 in the Tixel arm- patient's report will be collected since the 
last treatment done. 
• Before treatment 1, only for 10 patients randomized to a sub-set of the Tixel arm: Cornea 
OCT and coded images upload to EDC and/or SharePoint. OCT assessment should be 
performed before any corneal testing. 

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The following tests may be done again before treatment #1, only if treatment is being done 
on a different day than baseline exam, at the discretion of the investigator (these tests will 
be done prior to treatments 2 and 3 for the Tixel arm): 
• Slit Lamp for Anterior Segment 
• Lid Margin Abnormalities 
• Eyelid Margin Assessment 
1. Eye makeup shall be removed.  
2. The device shall be prepared for use in accordance with the Instructions for Use 
(IFU)/User Manual for the device to which the patient is randomized. An IFU/User 
Manual is packaged with each device that will be used in the study. 
3. For the LipiFlow treatment- Anesthetic eye drops shall be applied as per the Testing 
Methodologies for CLN 0798 study (CLN_0802). 
4. For the Tixel treatment-Anesthetic cream/gel may be applied only on the eyelids 
according to the investigator discretion.  
5. Therapy shall be delivered in accordance with the IFU/User Manual for the device to 
which the patient is randomized. Refer to the Testing Methodologies for CLN 0798 
study (CLN_0802) for more information. 
6. For Tixel device treatment, the following zones will be treated at the following 
Parameters: Small tip, 6 milliseconds pulse duration, 400µm protrusion, single pulse in 
the following order:  
• 5 shots nasal, medial, temporal region directly below/above lid margin next to 
each other (Figure 4) 
• 5 shots a little lower/higher (Figure 4) 
 
Figure 4-Treatment Zones With Tixel 
7. Representatives from the Sponsor may be present during the study visits when required.  

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8. Throughout the treatment visit, patients will be assessed for any adverse events , including 
for development of entropion or ectropion, floppy eyelids, and lash integrity assessment.  
9. Following treatment, patients will be assessed for the following:  
• Discomfort and Pain from the treatment (Tixel or LP) using the questionnaires 
in Appendix C.  These are visual analogue scale (VAS) questionnaires using a 
scale from 0-10 to assess eye discomfort and pain.  Both questionnaires are to 
be self-assessed by the patient immediately following treatment. 
• Slit Lamp Evaluation of Anterior Segment Health 
• Corneal Fluorescein Staining Slit Lamp Evaluation 
• Conjunctival staining Lissamine green 
• Intraocular Pressure 
• Assessment of Adverse Events 
10.  Post Treatment instructions following Tixel treatment: 
• Post Treatment instructions sheet will be given to the patient at baseline. The patient 
will adhere to the instructions following each treatment. 
• Patients should be aware that post treatment erythema, edema and some discomfort of 
the treated areas are possible and should not be a cause for concern.  
• It is not recommended to apply moisturizing creams for 24 hours after treatments. 
• No makeup, serum, toner or moisturizer with acids or “corrective” ingredients should 
be applied for at least 48 hours after treatment or until crusts have disappeared. It is 
preferable to apply non-perfumed makeup. 
• The patient should not tan in the treated area for at least 4 weeks after treatment. If sun 
exposure is necessary for short periods (up to 1 hour), a high SPF (at least 50 SPF) 
sunscreen must be worn on the lower and upper eyelids and sunglasses and a hat worn. 
Crusted skin should not be exposed to sun at all. 
• Rubbing, scrubbing and scratching the skin in the treated area should be avoided. Any 
tiny scabs (if present) should not be peeled away. 
• Avoid any exposure to chemical substances (such as direct exposure of the skin to 
cleaning substances) for at least a week after treatment. 
• Avoid exposure to dust and airborne dirt for at least a week after treatment.  
• Refrain from any sport, especially swimming and/or any other activity involving 
sweating, for at least a week after treatment. 
• Avoid exposure to heat (sauna stay, hot showers, etc.) for at least a week after treatment. 

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6.6 
4-Weeks Follow-Up Visit 
Patients will be required to return to the site 4 weeks (+/- 7 days) after the last treatment for the 
following assessments: 
• OSDI (administer first, self-assessed) 
• Cornea OCT- (only for the same 10 patients, in the Tixel group who performed 
the test at baseline). Images will be coded with site number, patient screening 
number, visit number and left/right eye and will be uploaded to EDC and/or 
SharePoint. OCT assessment should be performed before any corneal testing 
• Concomitant systemic and ophthalmic medications 
• Patient's report of the daily usage (frequency and dose) of eye lubricants since 
the last treatment 
• Uncorrected distance visual acuity  
• Corrected distance visual acuity 
• Keratometry 
• Slit Lamp for Anterior Segment Health 
• Lid Margin Abnormalities  
• Eyelid Margin Assessment  
• TBUT (must be performed by a masked rater) 
• Corneal Fluorescein Staining Slit Lamp Evaluation 
• Conjunctival staining Lissamine green 
• Meibomian Gland Assessment and Scoring (must be performed by a masked 
rater) 
• Intraocular Pressure  
• Assessment for Adverse Events 
6.7 
12-Weeks Follow-Up Visit 
Patients will be required to return to the site 12 weeks (+/-14 days) after the last treatment for 
the following assessments: 
• 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 
• Uncorrected distance visual acuity 

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• Corrected distance visual acuity  
• Keratometry  
• Slit Lamp for Anterior Segment Health  
• Lid Margin Abnormalities  
• Eyelid Margin Assessment 
• TBUT (must be performed by a masked rater) 
• Corneal Fluorescein Staining Slit Lamp Evaluation 
• Conjunctival staining Lissamine green 
• Meibomian Gland Assessment and Scoring (must be performed by a masked 
rater) 
• Intraocular Pressure 
• Assessment for Adverse Events 
 
 STATISTICAL CONSIDERATIONS  
7.1 
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. 
7.2 
Analysis Populations 
• Intent-to-Treat Population: The intent-to-treat (ITT) population includes all randomized 
patients. The primary and secondary efficacy analyses will be performed on the ITT 
population. Patients will be analysed as randomized.  
• Per Protocol Population: The per protocol (PP) population includes all patients who 
have at least one follow-up visit, complete all the treatments as randomized, and have 
no major protocol deviations. Patients will be analysed as treated. 

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• Safety Population: The safety population will include all treated patients. The safety 
population will be analysed for all safety assessments. Patients will be analysed as 
treated. A summary table of number (%) of patients in each analysis population/set will 
be provided. 
 
7.3 
Demographic and Baseline Characteristics 
Descriptive statistics or frequency tabulation will be provided for demographic and baseline 
characteristics, such as age, gender, race, and ethnicity. 
 
7.4 
Effectiveness Analyses  
- 
Primary endpoint 
The change from baseline at 4 weeks in TBUT in both study arms 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 change within each study group. 
Ho: µh – µc < 1.5 
HA: µh – µc ≥1.5 
where µ4w and µbase are the mean at 4 weeks and at baseline, respectively. 
- 
Secondary effectiveness endpoints 
• The change from baseline in the TBUT at 4 weeks will be analysed for non-inferiority 
with a margin of 1.5 using a one-sided two-sample t-test. The non-inferiority hypothesis 
set will be: 
Ho: µh – µc > 1.5 
HA: µh – µc ≤1.5 
where µt and µc are the mean changes from baseline for Tixel and control, respectively. 
Thus, the upper limit of the two one-sided 97.5% CI must be < 1.5 in order to 
demonstrate Tixel non-inferiority.  
• The change from baseline at 12 weeks in TBUT 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 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 

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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 change from baseline at 4 and 12 weeks in the MGS score 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 change within each study group. 
 
7.5 
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. Missing data in MGS score at 4 weeks will be imputed 
sequentially using multiple imputation (MI) technique. The imputation model will include age, 
gender and MGS score at earlier timepoints. 
7.6 
Interim Analysis 
No interim analyses are planned for this study. 
7.7 
Sample Size Justification 
15 patients will be enrolled in each treatment group. 
Sample size rationale: 
The sample size calculation was based on an expected change from baseline at 4 weeks in 
TBUT score of 1.5 seconds with a standard deviation of 1.9 seconds within each study group. 
Sample size justification: 
A sample size of 15 will have 80% power to detect a difference in means of 1.5 assuming a 
standard deviation of differences of 1.9 (effect size of 0.78), using a paired t-test with a 0.05 
two-sided significance level. 
Reference: 
O'Brien, R.G., Muller, K.E. Applied Analysis of Variance in Behavioral Science Marcel 
Dekker, New York (1993) Chapter 8 pp. 297-344 
7.8 
Poolability Analysis  
Patient demographic characteristics and background variables shall be summarized. To ensure 
poolability in case of more than one site, primary effectiveness will be analysed by site.  

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7.9 
Safety Analyses  
The incidence rate of device-related adverse events will be calculated along with 95% CI. The 
reporting period is from baseline through the last study visit. 
Secondary safety endpoint: 
• The evaluation of discomfort and pain will be summarized in appropriate tables by visit. 
• Changes from baseline in ocular surface staining, and intraocular pressure will be 
calculated along with 95% CI by study group and visit. 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 the study group. 
• Cornea OCT evaluation to detect changes (cornea thickness, cornea deamination) 
following treatment. Changes in Cornea OCT evaluation will be summarized in 
descriptive tables for the Tixel group. 
Adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA, most updated version) terminology and presented in tables by System Organ Class 
(SOC) and Preferred Term (PT).  
AE data will be listed individually and summarized by SOC and by PT within a system organ 
class. 
Treatment-emergent adverse events (TEAEs) are those with onset after initiation of study 
intervention or if occurring prior to initiation of study intervention, worsened after initiation of 
study intervention. Only treatment-emergent events will be summarized. All events in the 
clinical database regardless of when they occurred will be provided in a data listing. Definitions 
of adverse events, serious adverse events, and categorizations of events can be found in 
Appendix D. 
An overall summary will be presented which gives the number and percentage of patients that 
experienced any TEAE (overall, ocular, and non-ocular), experienced any treatment related 
TEAE (overall, ocular, and non-ocular), permanently discontinued treatment due to a TEAE 
(overall, ocular, and non-ocular), interrupted treatment due to a TEAE (overall, ocular, and non-
ocular), experienced a treatment emergent serious TEAEs (overall, ocular, and non-ocular), and 
that died. 

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A listing of serious TEAEs will be provided. Continuous safety endpoints shall be summarized 
using summary statistics such as means, medians, standard deviations, minima, maxima, and 
relevant percentiles.