Meibomian Gland Dysfunction Treatment
Phase: NA
Conditions: Meibomian Gland Dysfunction, Dry Eye
Sponsor: Indiana University

Meibomian Gland Dysfunction Treatment: 
Study Protocol
 NCT Number: NCT04229888 
Document Date: January 27, 2020  

CONFIDENTIAL STUDY PROPOSAL (v. 2020-JAN-27) 
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TITLE: Subject Masked Clinical Evaluation of Thermopulsation Treatment 
(Lipiflow) for Meibomian Gland Dysfunction  
INVESTIGATORS:  Anna A. Tichenor, Denise Howard, Jennifer Pence, Ping Situ, 
Carolyn Begley 
INVESTIGATION SITE:  Indiana University 
STUDY OVERVIEW 
Dry eye is a multifactorial chronic condition reducing quality of life by vision limitations 
and discomfort. LipiFlow, an FDA approved thermal pulsation treatment device, was 
designed to treat MGD related lipid deficiency evaporative dry eye. In previous studies, 
Lipiflow has been proven efficacious over standard dry eye therapies. However, many 
studies were limited in that the subject receiving treatment was aware of the difference 
and could potentially introduce bias for the newer technology. The current study aims to 
investigate the efficacy of Lipiflow when compared to a simulated placebo treatment. The 
impact on ocular health and perceived symptoms will also be evaluated. 

CONFIDENTIAL STUDY PROPOSAL (v. 2020-JAN-27)  
 
 
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RATIONALE AND SIGNIFICANCE: Meibomian gland dysfunction is a common 
condition in clinical practice coinciding with reduced tear film stability and patient 
complaints of dryness and irritation. The number of therapeutic devices and clinical 
trials focused on this complex issue are growing. Although many clinical trials show the 
increased efficacy of thermal pulsation treatment options compared to traditional 
therapy, subjects in all of these studies were aware of the treatment they were 
undergoing; thus, the possibility for subject bias was high.  
 
STUDY AIM: The current study aims to systematically investigate the efficacy of Lipiflow 
treatment in patients with Meibomian gland dysfunction. This study will compare a single 
Lipiflow treatment to a single simulated placebo treatment in the same patient to mask 
subjects from any potential bias for newer technology. 
 
STUDY DESIGN 
The study is a prospective, clinical trial, comparing the difference in results between 
Lipiflow and a placebo control (subject masked to treatment), and also comparing 
treatment versus no treatment between eyes (subject not masked to treatment). 
There will be 4 study visits in this investigation, an initial screening visit, a placebo 
treatment visit, a Lipiflow treatment visit and an exit/assessment visit (in that order).  
Potential subjects will be called and administered a telephone screener for dry eye 
symptoms, medical and ocular history to exclude those with previous ocular surgery, 
etc., before being scheduled for Visit 1. If eligible based on the telephone screener, time 
and day of visit schedule will be discussed with subject to make an effort to keep 
appointments at the same time of day, and all visits will be tentatively scheduled for the 
subject. Visit 1 will check remaining eligibility criteria including presence of meibomian 
gland dysfunction and review criteria from telephone screener to confirm eligibility. 
 
SUBJECT POPULATION 
Up to 16 adults with meibomian gland dysfunction and symptoms of dry eye disease will 
be enrolled in this study. The minimum sample size requirement based on sample size 
calculations is 14 subjects.  
 
SUBJECTS 
Inclusion Criteria:  
1. Evidence of Meibomian gland obstruction in both eyes 
a. Number of functional meibomian glands < 6 in the lower eyelids of both 
eyes (that is, number of meibomian glands yielding liquid secretion with 
MGE less than 6) (ref: Korb DR, Blackie CA: Meibomian gland diagnostic 
expressibility: correlation with dry eye symptoms and gland location. 
Cornea 2008, 27(10):1142-1147.) 
b. At least 10% dropout total in both eyes for both eyelids as seen on 
meibography images 
2. Remaining Meibomian glands not severely truncated. 
3. Reported dry eye symptoms by DEQ-5 score > 6 

CONFIDENTIAL STUDY PROPOSAL (v. 2020-JAN-27)  
 
 
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4. Willingness and ability to adhere to the instructions set forth in this clinical 
protocol. 
5. At least 18 years of age 
 
Exclusion Criteria:  
1. Systemic Conditions 
a. Ocular or systemic conditions that could potentially the limit effectiveness 
of the study treatment 
b. Beginning new oral or other systemic medications or nutritional 
supplements or changing dosages within the past 3 months  
2. Ocular 
a. Remaining Meibomian glands severely truncated/> 90% total meibomian 
gland dropout on meibography on upper + lower eyelids in each eye  
b. Previous Lipiflow treatment 
c. Beginning new ocular medications or changing dosages within the past 3 
months  
d. Altering dry eye treatment, including, but not limited to, artificial tears, 
Bruder mask, ophthalmic or allergy drops and lid hygiene within the past 3 
months 
e. Previous ocular surgery, trauma, herpes, recurrent inflammation, punctal 
plugs or occlusion within 3 months of the baseline examination 
f. Ocular surface abnormality potentially compromising corneal integrity in 
either eye 
g. Active ocular infection in either eye or evidence of latent infections, such 
as Herpes simplex or zoster 
h. Ocular surface or eyelid abnormalities that preclude use of Lipiflow device 
i. Participating in another ophthalmic clinical trial involving a therapeutic 
drug or device within the past 30 days 
j. Habitual contact lens wear within 3 months 
3. Pregnant or nursing by self report 
 
STUDY VISITS AND PROCEDURES 
There will be 4 study visits: Baseline/Screening, Sham treatment, Lipiflow treatment, 
Final visit.  
 
Visit 1 (screening) 
1. Subjects will complete these symptom questionnaires in the following order, for 
each eye individually using iPAD in Qualtrics:  
a. DQ 
b. CSQ 
Visit 1: 
Baseline/
Screening
1 - 7 
days
Visit 2: Sham 
Treatment
14 ± 5 
days
Visit 3: Lipiflow 
Treatment
14 ± 5 
days
Visit 4: Final 
Visit

CONFIDENTIAL STUDY PROPOSAL (v. 2020-JAN-27)  
 
 
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c. DEQ-5 (score must be >6 to continue in study) (1 month recall) 
2. Medical and Eye Health History 
3. Visual Acuities at Distance (best corrected, LogMar) 
4. Slit lamp examination of ocular surface and lids (minimally invasive) 
a. Subjects must show Meibomian gland obstruction  
b. No evidence of ocular infection, surgery or trauma or any other 
abnormalities that would preclude Lipiflow treatment (subject excluded) 
5. LipiView 
a. Lipid layer thickness 
b. Meibography (upper and lower eyelids) 
6. Study Procedures 
a. FBUT (video recorded, 3x) 
b. Corneal Staining (photo) 
c. Conjunctival Staining (photo) 
7. Determine eligibility and tell subject 
 
a. Both eyes need to qualify 
8. Eye to be tested chosen by random number chart (Jenn) 
a. Investigator is masked  
 
 
Visit 2:  Sham Treatment (1 – 7 days after Visit 1, same time of day if possible) 
1. Subjects will complete these symptom questionnaires in the following order using 
iPAD.  
a. CSQ:  Each eye separately 
b. DEQ-5 (score must be >6 to continue in study):  each eye (1 month recall) 
2. Visual Acuities (BCVA, LogMar) 
3. LipiView 
a. Lipid layer thickness 
4. Slit lamp examination of ocular surface and lids 
a. Overall health: grading scales and measures 
b. FBUT (video), corneal and conjunctival staining 
5. Study Procedures:  before treatment 
a. Video gland expression with slit lamp biomicroscope, using meibomian 
gland expressor 
6. Sham treatment to tested eye 
a. Sham treatment on tested eye 
b. Tape and patch other eye 
c. Anesthetic in both eyes 
7. CSQ for each eye.  Questionnaire about treatment comfort 
8. Study Procedures:  after treatment 
a. Lipiview:  lipid layer thickness OU 
b. Slit lamp ocular health examination OU 
c. Video tear breakup 3x 
d. Video gland expression with slit lamp biomicroscope, using meibomian 
gland expressor 
9. Make sure subject is scheduled for next appointment (14 ± 5 days) 
 
Visit 3:  Lipiflow Treatment (14 ± 5  days later, same time of day if possible) 

CONFIDENTIAL STUDY PROPOSAL (v. 2020-JAN-27)  
 
 
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1. Subjects will complete these symptom questionnaires in the following order.  
a. CSQ:  Each eye separately 
b. DEQ-5:  each eye (since the last visit) 
2. Visual Acuities (BCVA, LogMar) 
3. LipiView 
a. Lipid layer thickness 
4. Slit lamp examination of ocular surface and lids 
a. Overall health: grading scales and measures 
b. FBUT (video), corneal and conjunctival staining 
5. Study Procedures:  before treatment 
a. Video gland expression with slit lamp biomicroscope, using meibomian 
gland expressor 
6. Placebo treatment to tested eye 
a. Lipiflow on tested eye 
b. Tape and patch other eye 
c. Anesthetic both eyes 
7. CSQ for each eye.  Questionnaire about treatment comfort. 
8. Study Procedures:  after treatment 
a. Lipiview:  lipid layer thickness OU 
b. Slit lamp ocular health examination OU 
c. Video gland expression with slit lamp biomicroscope, using meibomian 
gland expressor 
9. Make sure subject is scheduled for next appointment (14 ± 5 days) 
 
Visit 4:  Final/Exit Visit (14 ± 5 days) 
1. Subjects will complete these symptom questionnaires in the following order.  
a. CSQ:  Each eye separately 
b. DEQ-5:  each eye (since the last visit) 
2. Visual Acuities 
3. LipiView 
a. Lipid layer thickness 
b. Meibography 
4. Slit lamp examination of ocular surface and lids 
a. Overall health: grading scales and measures 
b. FBUT (video), corneal and conjunctival staining 
5. Study Procedures 
a. Video gland expression with slit lamp biomicroscope, using Meibomian 
Gland Expressor 
6. The subject will be provided information on which eye received treatment at the 
time of exit.  
7. Subject exits study.  Can have Lipiflow on other eye, not as part of the study. 
 
Equipment: 
1. Slit lamp biomicroscope. 
a. A microscope with a bright light and magnification that can be used to take 
a close look at the structures of the eye. The binocular aspect provides a 
stereoscopic view of the eye structures. 
2. Lipiview Ocular Surface Interferometer 

CONFIDENTIAL STUDY PROPOSAL (v. 2020-JAN-27)  
 
 
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a. The Lipiview is a non-invasive device that can capture digital images of 
interferometric observations of the tear film and of the meibomian glands 
under near-infrared illumination. It can measure the absolute thickness of 
the tear film lipid layer. It will also be used to image glands to determine 
the level of obstructed glands, gland loss, and potential for benefit from 
thermal pulsation treatment.  
3. Lipiflow Thermal Pulsation System 
a. The LipiFlow is a device used for applying localized heat and pressure in 
adult patients with conditions such as meibomian gland dysfunction. It is 
an in-office procedure that provides controlled heat to the inner surface of 
the eyelids and pulsating pressure to the outer eyelid. This heat and 
pressure facilitates release of lipid, or meibum, from the meibomian glands 
to liquify and clear clogged glands. The procedure lasts 12 minutes and 
uses a single– use sterile dome shaped activator that applies heat and 
pressure to the Meibomian glands to liquefy and clear clogged glands.  
4. Describe Placebo treatment. 
5. Meibomian Gland Evaluator for expression from meibomian glands 
 
 
STUDY OUTCOMES 
 
Primary outcome: Change in DEQ-5 score from V3 to V4 for LipiFlow treatment when 
compared to change in DEQ-5 score from V2 to V3 for sham treatment.  
 
Secondary outcome: Change from V3 to Visit 4 in meibomian gland score (meibomian 
glands evaluated on the lower eyelid using MGE. 5 glands in 3 regions (nasal, central, 
temporal) evaluated and scored from 0 to 4 for a max score of 60 in each eye. MGS 
scale 0 = clear, 1 = cloudy, 2 = granular, 3 = pastelike, 4 = obstruction)  
 
Exploratory outcomes: Change in TBUT, LLT 
 
CLINICAL TRIALS REGISTRATION 
This trial will be registered on clinicaltrials.gov. The description of this registration will 
only describe the primary outcome measures, not any secondary or exploratory 
measures.   
 
ADVERSE EVENTS 
All adverse events that occur during the study will be reported by the investigators.  
 
DATA HANDLING 
Data will be collected and recorded using case report forms. The data will then be 
entered into an electronic system stored on a password protected and encrypted server. 
Data will be stored for XX years.  
 
 
STATISTICAL ANALYSES 
Sample Size Calculation 
 

CONFIDENTIAL STUDY PROPOSAL (v. 2020-JAN-27)  
 
 
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The overall sample size estimate for this study is based on the primary outcome 
measure of change in DEQ-5 score from V3 to V4 for Lipiflow treatment. We 
hypothesized that the change in DEQ-5 score would be greater for the Lipiflow 
treatment when compared to the sham treatment.  The sample size was calculated with 
80% power to detect a mean difference of 3 points, with a standard deviation of 3.5 
points on the DEQ-5 questionnaire based on previous studies using a type 1 error of 
5%. This power calculation resulted in 14 patients. In order to ensure that the study is 
powered relative to any loss to follow up, we will recruit a total of 16 patients. 
 
Analysis 
A repeated measures analysis of variance (repeat measure ANOVA) will be used for 
statistical analysis of crossover and treatment effects. Pearson correlation analysis will 
be performed to evaluate the relationship between Lipiflow treatment and clinical 
measures. P values< 0.05 will be considered statistically significant.