Combination of 0.09% Cyclosporine and Intense Pulsed Light (IPL) Therapy for the Treatment of Dry Eye Disease in Symptomatic Contact Lens Wearers: a Sham-Controlled Randomized Clinical Trial
Phase: PHASE3
Conditions: Dry Eye, Contact Lens Complication
Sponsor: Université de Sherbrooke

STUDY PROTOCOL 
 
 
 
 
 
 
 
 
 
Oﬃcial 1tle: Combina)on of 0.09% cyclosporine and IPL therapy for the 
treatment of dry eye disease in symptoma)c contact lens wearers: a sham-
controlled randomized clinical trial 
 
Authors : Éric Lor(e-Milner, Langis Michaud, Patrick Boissy 
 
NCT number : not assigned yet 
 
Document date : April 22nd, 2024 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

INTRODUCTION 
Background and rationale  
 
Dry eye disease is a complex and mul(factorial pathology in which the tear ﬁlm is 
compromised. Inﬂamma(on and changes to the tear ﬁlm (instability and 
hyperosmolarity) are central to this condi(on1. Dry eye disease is very common, with an 
es(mated global prevalence of 11.59%2 although some analyses conclude to 50% of 
some popula(ons suﬀering from dry eye3. The condi(on has been tradi(onally classiﬁed 
in two subtypes: aqueous tear deﬁciency (secondary to a deﬁcit of produc(on by the 
lacrimal gland) and evapora(ve disease (secondary to a deﬁcit of the lipid layer of the 
tear ﬁlm), but research has shown that more than 80% of individuals with dry eye have 
mixed or predominantly evapora(ve dry eye disease and that, when the condi(on 
progresses, almost all pa(ents present characteris(cs of both subtypes4. Hence, this 
classiﬁca(on has lost of its importance in the new approach to the disease1. Meibomian 
gland dysfunc(on (MGD) is one of the condi(ons that is most frequently associated with 
dry eye disease. It is the source of changes both in quan(ty and quality to the meibum 
that is released on the ocular surface and leads to evapora(ve dry eye as well as 
altera(ons of the ocular surface5. The prevalence of MGD has been recently computed 
between 21.2% and 29.5% in subjects of African and Caucasian race and higher among 
Arabs, Hispanics6 and Asians7. Many risk factors exist for dry eye disease and MGD, 
including age and usage of contact lens8. 
 
SoZ contact lenses are used by hundreds of millions of people to correct myopia, 
hyperopia, as(gma(sm and presbyopia9. The wear of contact lens, however, has the 
poten(al to create or worsen dry eye signs and symptoms10. Despite recent 
technological breakthroughs that have led to more sophis(cated lens material, a large 
number of contact lens wearers s(ll suﬀer from dry eye. A compara(ve study has found 
that 39% of North-American wearers can be categorized as symptoma(c of contact lens 
dry eye11 and the propor(on of uncomfortable users increases with age12. A soZ contact 
lens that is placed on the ocular surface disturbs the normal homeostasis of the tear ﬁlm 
by spli^ng it in two compartments13. Contact lens wear can increase evapora(ve dry 
eye14 by weakening the lipid layer, which leads to decreased stability10 of the tear ﬁlm 
and increased evapora(on15. It also contributes to aqueous dry eye e(ology14 by 
reducing the tear volume16. The wear of contact lens has also been shown to have a 
damaging eﬀect on meibomian glands17, 18 and, in some cases, on the conjunc(val goblet 
cells8. Arguments also support the role of contact lens in the inﬂamma(on of the ocular 
surface19, 20, even in asymptoma(c pa(ents21. Thus, dry eye disease associated with 
contact lens wear is a complex condi(on that implies many diﬀerent mechanisms. 
 
Cyclosporine A is a pep(de produced by a fungus that has been used systemically 
for decades for its potent immunomodulatory eﬀects22. Usage for dry eye disease in a 
topical 0.05% oil-based formula(on has been common since the early 2000s23. On the 
ocular surface, cyclosporine acts by inhibi(ng calcineurin, which subsequently blocks the 
ac(va(on of T cells and prevents the release of cytokines, therefore reducing 
inﬂamma(on22. It has been shown to increase tear volume, goblet cell density and to 
reduce surface staining as well as symptoms in dry eye pa(ents24-27. Divergent results 

have been observed on contact lens wearers28, 29, although one study has found an 
ampliﬁed eﬀect on contact lens wearers symptoma(c of dry eye when combining 
essen(al faay acid supplements with topical cyclosporine30. Despite having been shown 
useful in the management of dry eye disease, the oil-based formula(on is considered 
having a low bioavailability31. A new cyclosporine eyedrop has been approved in Canada 
and the USA in the recent past years and is based on nanomicelle technology with a 
concentra(on of 0.09%32.  This nanomicellar formula(on could be more eﬀec(ve in 
delivering the cyclosporine to the (ssues33 and have been shown to reduce ocular 
surface staining34, 35, to increase tear volume36, 37 and to be safe38. Adverse events that 
are known to this product are mild, such as transient pain at ins(lla(on for about 23% of 
pa(ents38. 
 
Intense pulsed light (IPL) is a therapeu(c process that has been used for many 
years in dermatology and esthe(cs39. The noncoherent pulses of light produce photo-
biochemical eﬀects and, in the treatment of dry eye disease, the applica(on on the skin 
around the orbit to produces these eﬀects on the meibomian glands and their 
surrounding (ssue40. The mechanisms by which IPL improves signs and symptoms of dry 
eye are not fully understood, but the mel(ng of the meibum, the clogging of 
telangiecta(c inﬂammatory vessels, the reduc(on of epithelial turnover, the 
improvement in the collagen synthesis, a mitochondrial ac(vity enhancement (photo 
modula(on), and the destruc(on of parasi(c and bacterial species are the main 
theore(cal explana(ons41-43. IPL has been shown to be an eﬀec(ve therapeu(c op(on to 
manage MGD44-47. Dozens of studies have shown that IPL reduces dry eye symptoms, 
increases tear break-up (me, improves the secre(ng func(on of the glands as well as 
the quality of the meibum and reduces corneal staining43, 48. The op(mal number of IPL 
sessions for an eﬀec(ve dry eye treatment have not been established, but many studies 
use 3 sessions, which is the star(ng point of many clinicians49. IPL is oZen combined 
with meibomian gland expression to maximize the therapeu(c eﬀects50; however, 
controlled studies have shown that IPL is largely responsible of these eﬀects and that it 
is the core mechanism of this combina(on51-53. Two studies have observed the eﬀect of 
IPL on contact lens users, with the conclusion that it is an eﬀec(ve treatment for this 
popula(on54, 55. IPL is considered to be a safe treatment56, but localized redness and 
burning sensa(on or tenderness can occur following the treatment43. Loss of eyelashes 
have been reported52. More severe events, although rare, can include skin 
depigmenta(on and keloids43. 
 
Objectives 
The primary objec(ve of this study is to determine whether the combina(on of 0.09% 
cyclosporin ocular nanomicellar drop treatment for 16 weeks and three IPL sessions is 
more eﬃcient than the combina(on of 0.09% cyclosporin ocular nanomicellar drop with 
three sham IPL sessions in relieving the symptoms of symptoma(c soZ contact lens 
wearers. The secondary objec(ve is to do the same comparison but when studying signs 
of dry eye (TBUT, NIBUT, tear osmolarity, tear meniscus height, meibomian gland 

atrophy, corneal staining and conjunc(val staining) in soZ contact lens wearers. The 
third objec(ve of this study is to explore the eﬀect of Cequa alone on symptoms and 
signs of contact lens wearers that suﬀer from dry eye. The fourth objec(ve is to assess 
the security proﬁle of the treatments on soZ contact lens wearers. 
 
Hypothesis 
It is believed that the experimental group (receiving Cequa and IPL) will have a greater 
improvement in symptoms of dry eye while wearing contact lenses when compared to 
the control group. Previous studies have shown that cyclosporine A can improve dry eye 
symptoms27, 57, 58. Even though results using the previous formulation on contact lens 
wearers have been modest28-30, the proven role of inflammation in contact lens dry 
eye21, 59-61 theoretically supports that its new formulation could help the signs and 
symptoms of contact lens dry eye. It will be combined to a MGD treatment, which has 
been shown in the past to enhance effects on contact lens wearers30. IPL has been 
shown in multiple studies to improve dry eye signs and symptoms43-48. 
 
Specifically, tear film stability is expected to be improved in the experimental group 
when compared to the control group, given the proven effect of IPL on meibomian 
function and tear film stability44-46, 51, 52, 62-65. No significant differences in corneal 
staining and conjunctival staining scores between the two groups are expected, as the 
results of studies testing IPL on non-CL wearers are very sparse on these variables, and 
contact lens wearers frequently have mechanical or mild toxic causes (maintenance 
solution) that maintain these corneal or conjunctival epithelial defects. No significant 
difference in tear osmolarity is expected between the two groups either, as the results 
of studies testing IPL on non-CL wearers are very sparse on this variable. No significant 
difference in gland atrophy score in either group is also expected, as the results of 
studies testing the IPL on LC non-carriers are very sparse regarding this variable. Also, 
the researchers' view is that a gland that is atrophied may recover the part that was 
recently in the process of atrophy, resulting in a slight improvement on meibography, 
but the morphological changes caused by atrophy are essentially permanent. It is 
expected also that no serious adverse effect will happen in none of the two groups, as 
both treatments have been shown in previous studies to have good security profiles36, 
56. No significant difference is thus expected between the two groups regarding adverse 
effects. 
 
Trial design 
This study is a pre-post interven(onal study randomized on the IPL interven(on; it is a 
superiority randomized clinical trial sham-controlled. It will be composed of two groups 
of equal sizes (1:1 alloca(on ra(o). 
 
METHODS 
Study setting 

This study will take place in an optometric private prac(ce clinic in Sherbrooke, Canada. 
Data will be stored and analyzed in a university research center in the same city. 
 
Eligibility criteria 
The inclusion criteria for this study are the following: 
- 
18 years or older and able to consent 
- 
Silicone-hydrogel contact lens wearers (minimum wear of 1 day/week for 4 
hours) since at least 2 years 
- 
Pa(ents that use monthly, bi-monthly or daily replaceable soZ contact lenses 
- 
Symptoma(c contact lens wearers (f-CLDEQ-8 score of 12 or above) 
 
The exclusion criteria for this study are the following: 
- 
Present or past usage of Cequa 
- 
Usage of cyclosporin drop in the past 6 months 
- 
Known cyclosporin intolerance 
- 
Current pregnancy or breasjeeding 
- 
IPL or cyclosporin contraindica(on (ocular HSV infec(on history, ac(ve ocular 
infec(on, usage of medica(on that induces sensi(vity to light, epilepsy, history of 
skin cancer in the treatment area, pigmented lesion in the treatment area, keloid 
scar in the treatment area, taaoo in the treatment area, vi(ligo) 
- 
Refrac(ve surgery in the past 12 months 
- 
Thermal pulsa(on MGD treatment in the past 12 months 
- 
Usage of topical glaucoma treatment 
- 
Con(nuous wear of contact lenses (sleeping with contact lenses) 
- 
Poor ﬁt of contact lenses (decentered or excessive movement) 
- 
Giant papillary conjunc(vi(s 
Who will take informed consent? 
All procedures will be performed by the same licensed optometrist. This researcher or 
another member of the research team (if par(cipant is, for instance, a pa(ent of the 
optometrist) will collect informed consent. 
 
INTERVENTION 
Explanation for the choice of comparators 
It was decided that a sham IPL procedure would take place. To perform such a sham, a 
piece of hardened plas(c has been designed with a 3D printer that covers the prism of 
the IPL, blocking the light’s energy from reaching the skin of the par(cipant. A 5mm 
space between the surface of the prism and the piece of plas(c with openings on the 
side will allow the light to be ejected to the side. This will both prevent reﬂec(on of the 
energy, which could have damaged the IPL and will allow for the par(cipant to see some 
light through his eyeshields. This will assure that the visual and audi(ve experience of 
par(cipants in the sham group is very close to that of a real IPL experience. Of course, 

par(cipants will have protec(ve shields on their closed eyelids, which will make them 
unable to see the piece of plas(c. Figure 1 shows a picture of the blocker. 
 
  
Figure 1: Picture of the IPL ﬁlter over the M22 Lumenis prism 
Interven7on descrip7on 
Par(cipants will receive drops of 0.09% cyclosporine twice a day for 16 weeks in both 
eyes. The product is distributed in single-dose vials, which will require the use of a 
diﬀerent vial for the morning and the evening dose. Instruc(ons will be given to the 
par(cipants that they leave a (me gap of 15 minutes between the ins(lla(on of the 
cyclosporine drops and the inser(on of their contact lenses. In the same way, it will be 
instructed that par(cipants wait 15 minutes aZer removal of the contact lenses before 
ins(lla(on if the drops. 
The second interven(on will be a standard IPL procedure for the experimental group, as 
described by Toyos62. First, protec(ve opaque shields will be placed on the closed eyelids 
of the par(cipants, closely under the inferior lid margin. Then, protec(ve IPL gel will be 
applied in the treatment zone, that will go from the right temple to the leZ temple, 
boarding the inferior limit of the shield and including the zone over the nasal bone. 
Se^ng of cooling of the IPL prism will be ac(vated and the 590nm ﬁlter will be placed in 
the handheld part of the IPL.  3 pulsa(ons per shot and cycles of 6-50 ms (pulse-pause) 
for each pulsa(on will be programed. Fluence of the IPL will be adjusted depending on 
the skin type (using the Fitzpatrick scale; type I receiving a ﬂuence of 16 J/cm2 and type 
IV receiving a ﬂuence of 13 J/cm2). 15 shots of IPL will be applied from one temple to the 
other, slightly overlapping each precedent shot (7 shots on each side and one central 
shot; see ﬁgure 2). This procedure will be repeated for a second passage, for a total of 30 
IPL shots on the treatment zone. 

  
Figure 2: Half of one passage of IPL treatment plan 
Criteria for discontinuing or modifying allocated interventions  
Either one of the interven(ons would be discon(nued for a par(cipant if a serious 
adverse event arose. Serious adverse events will be described in this study as event 
possibly linked to the interven(on that require medical management (prescrip(on of 
an(microbial or an(-inﬂammatory drugs, surgery) and/or that poses the threat of long-
term visual sequelae. It is expected that par(cipants feel a slight level of discomfort with 
both interven(ons (cyclosporine drops and IPL session), so this will not be a factor. 
Par(cipants’ will to stop the study would also be a mo(ve of discon(nua(on of the 
assigned treatment. In no case would a par(cipant be transferred to the other group of 
the study. 
Strategies to improve adherence to interventions 
Non-adherence could be a problem for the ﬁrst interven(on (cyclosporine eyedrops). To 
try and improve adherence, a courtesy call will be made by the research team 3 weeks 
aZer the beginning of the study. Par(cipants will also receive a ques(on by text message 
weekly to ask about the number of drops ins(lled in the last days, which could be a 
reminder to observe the treatment.  Concerning the IPL, it is not expected that 
adherence will be a problem since this interven(on is made in the clinic and only takes a 
few minutes. However, ﬁnancial compensa(on will be given to the par(cipants for their 
(me, which should help even more to ensure adherence to this treatment. 
 
Relevant concomitant care permitted or prohibited during the trial  
Par(cipants will be permiaed to con(nue any dry eye treatments that they are currently 
taking (besides those men(oned in the exclusion criteria). This includes use of ar(ﬁcial 
tears, lubrica(ng ointments, omega-3 supplements, warm compresses, lid hygiene, 
punctal plugs, etc.). However, the ini(a(on of new components of treatment will not be 
permiaed during the 4 months of the trial. 
Provisions for post-trial care  

Par(cipants from the study will be pa(ents of the prac(ce in which the optometrist that 
is the main inves(gator of this study works. Dry eye care will con(nue with this 
optometrist if the pa(ent wishes to pursue care with this optometrist or any other of the 
clinic. 
Outcomes  
The primary outcome of this study will be par(cipants’ symptoms of dry eye while 
wearing contact lenses. It will be collected at each visit using the f-CLDEQ-8 at every visit 
of every par(cipant. This French version of the CLDEQ-8 has shown to be valid, with an 
internal consistency of 𝛼= 0.929 and a high reliability (ICC=0.944)66. The use of the 
CLDEQ-8 is recommended by the Tear Film Ocular Surface Society (TFOS) panel67 to 
measure this outcome. For each par(cipant in a given group, the diﬀerence between the 
score at the beginning of the study (baseline) and at the end of the study (16 weeks) will 
be calculated. The mean diﬀerence of each group will be calculated and compared 
between groups. The CLDEQ-8 is a responsiveness tool that has been deemed eﬃcient 
to measure change in contact lens comfort in studies with a clinically important 
diﬀerence (CID) value of 3 points on 3768. Alterna(vely, ques(ons will be sent by 
electronic communica(on to the par(cipants twice weekly to ask about their perceived 
comfort while wearing contact lenses (scale 0-100). The use of such a global ra(ng scale 
of change is recommended by the TFOS panel67 and will allow for a diﬀerent, more 
con(nuous and global evalua(on of symptoms. In these electronic communica(ons, 
par(cipants will also be asked the amount of average wearing (me of their contact 
lenses in the past 3 to 4 days and their average daily use of ar(ﬁcial tears in the past 3-4 
days, which can be considered indirect markers of contact lens discomfort67. 
 
There are many secondary outcomes in this study: 
- 
Tear ﬁlm stability over contact lenses. This outcome will be measured with the 
Medmont E300 automated Tear Film Surface Quality (TFSQ) and NIBUT func(ons 
while the par(cipant is wearing his contact lenses. The average of 3 measures 
will be selected. It will be collected for each eye. 
- 
Tear ﬁlm osmolarity while wearing contact lenses. This outcome will be 
measured using the i-Pen, a portable osmometer which has been shown to be 
reliable69, valid and correlated with other signs and symptoms of dry eye70. The 
osmolarity will be collected at the inferior lid for both eyes. 
- 
Tear volume while wearing the contact lenses. This outcome will be measured 
using the tear meniscus height evalua(on of the Myah (Topcon) while the 
contact lenses are in place in each eye. This func(on averages 5 points across the 
tear meniscus to provide a value. The value of tear meniscus height while 
wearing contact lenses has been shown linked to comfort71 
- 
Tear ﬁlm stability. This outcome is used in a majority of studies on dry eye and 
will be collected by two manners. First, the automated TFSQ and NIBUT func(ons 
of the Medmont E300 corneal topographer will be performed on the tear ﬁlm 
(aZer removal of the contact lenses). It will also be collected by measuring the 
(me between opening of the eyes and a break in the ﬂuoresceine paaern of the 

tear ﬁlm. 30 seconds aZer a small amount of sodium ﬂuoresceine is ins(lled from 
a strip, video recordings from a slit lamp of the surface of the eye with cobalt 
ﬁlter from the slit lamp and a handheld yellow ﬁlter will be taken. The average of 
three measurements will be used.  
- 
Corneal and conjunc(val staining score. This outcome will be evaluated by 
ins(lling a dye in the eye. Fluoresceine will be used for corneal staining and 
lissamine green will be used for conjunc(val staining. Pictures of the cornea (with 
cobalt ﬁlter and handheld yellow ﬁlter) and the conjunc(va will be taken at the 
slit lamp and sent to the AOS soZware that objec(vely grades anterior segment 
imagery72. The conjunc(val pictures will be sent to observers blinded to the 
alloca(on of the par(cipant for grading. The Efron grading scale will be used, 
which is speciﬁc for contact lens complica(ons, widely used in clinic and one of 
the most reliable scales available73. Ocular surface staining scores have been 
recommended by the TFOS panel for studies on contact lens dry eye67. 
- 
Meibomian gland atrophy. This outcome will be evaluated by imaging the inferior 
and superior eyelids of each eye with the Lipiscan (Johnson & Johnson) of each 
par(cipant and having a blinded observer grade the meibomian score. The score 
will be established using Pult’s meiboscale, a reliable74 and repeatable75 scale. 
- 
Presence of adverse eﬀects. This outcome will be measured using a homemade 
ques(onnaire that asks about adverse eﬀects on both interven(ons (Cequa and 
IPL). The ques(onnaire contains yes/no ques(ons as well as open ques(ons, 
allowing par(cipants to report unexpected or unusual adverse eﬀects. 
- 
Best corrected distance visual acuity. This outcome is measured for security 
purposes only. It will be measured at each visit before any other ac(on is posed. 
Best corrected visual acuity is an indicator of good health of the ocular 
structures. 
- 
Intraocular pressure. This outcome is measured for security purposes only. No 
documented case of IOP rise following the intake of cyclosporin drops or IPL 
treatment is known, but in the presence of fairly new therapeu(c op(ons (Cequa 
and IPL), it was decided to measure the pressure. 
 
Par7cipant 7meline {13} 
 
 
STUDY PERIOD 
 
Enrolment 
Allocation 
Post-
allocation 
Close-out 
TIMEPOINT(Week) 
0 
8 
11 
14 
16 
ENROLMENT: 
 
 
 
 
 
Eligibility screen 
X 
 
 
 
 
Informed consent  
X 
 
 
 
 

Allocation 
 
X 
 
 
 
INTERVENTIONS: 
 
 
 
 
 
0.09% Cyclosporine 
(Cequa) 
 
 
 
 
 
IPL or Sham-IPL 
 
X 
X 
X 
 
ASSESSMENTS: 
 
 
 
 
 
f-CLDEQ-8 
X 
X 
X 
X 
X 
Use of artificial 
tears 
 
 
 
 
 
Contact lens wear 
hours 
 
 
 
 
 
0-100 comfort 
 
 
 
 
 
f-TBUT 
X 
X 
 
 
X 
NIBUT over SCL 
X 
X 
 
 
X 
NIBUT on tears 
X 
X 
 
 
X 
Tear osmolarity 
X 
X 
 
 
X 
Tear volume (TMH) 
X 
X 
 
 
X 
Corneal staining 
X 
X 
 
 
X 
Conjunctival 
staining 
X 
X 
 
 
X 
Meibography 
X 
 
 
 
X 
Adverse events 
questionnaire 
X 
X 
X 
X 
X 
Best-corrected 
Visual acuity 
X 
X 
X 
X 
X 
Intra-ocular 
pressure 
X 
X 
X 
X 
X 
 
Sample size 
The number of par(cipants needed to detect a signiﬁcant between the groups using the 
f-CLDEQ-8 was established by using data from prior studies54, 66, 76.  The standard 
devia(on of the sample on the f-CLDEQ-8 was es(mated by calcula(ng the standard 

devia(on of the por(on of the sample from the valida(on study of the f-CLDEQ-8 that 
had a score≥12. This approach was used because the popula(on from which the sample 
in both studies (the valida(on study and the study described in this ar(cle) will be drawn 
are very similar. The expected standard devia(on is 4.58. It was decided to use eﬀect size 
to compute sample size. It was decided that an expected eﬀect size of 0.80 would be 
used. This comes from subtrac(ng the eﬀect size for symptoms (pre-treatment vs post-
treatment) in the study on Cequa by Tauber et al., which was 1.2, from the eﬀect size 
(IPL vs sham) in the study of Yang et al., which was 2.0. The ra(onale for this calcula(on 
was that both groups will already have had the eﬀect from Cequa when receiving their 
IPL (or sham-IPL) treatment. 0.80 is also the theore(cal value for a large eﬀect size by 
Cohen. To detect a 0.8 eﬀect size between the two groups with a bilateral T-test for 
independent samples having a standard devia(on of 4.58, a total of 44 par(cipants 
(22/group) will have to be recruited. 
 
Recruitment 
Recruitment for this project will be made directly by the optometrists that prac(ce in 
the associate loca(ons that surround the clinical center where the research will take 
place (total of 18 optometrists). When they will see a pa(ent during an eye exam that 
seems to ﬁt the eligibility criteria, informa(on about the study will be given to the 
pa(ent and, if desired contact informa(on to the research team. Posters describing the 
study and including a QR code linked to the email address of the main researcher will 
also be put up in the optometry clinics of the associate loca(ons (6 clinics) for poten(al 
candidates to contact the research team.  
 
Assignment of interventions: allocation 
Sequence generation 
Alloca(on of the par(cipants to the two groups will be stra(ﬁed following the severity of 
the f-CLDEQ-8 score to avoid too much variability in this important factor in the 
amplitude of the eﬀect of the treatments77. The f-CLDEQ-8 will be established at the ﬁrst 
visit and par(cipants will be categorized as having moderate symptoms (score 12 to 17), 
severe symptoms (score 17 to 24) of very severe symptoms (score 25 or over). Alloca(on 
will be performed aZer the ﬁrst visit. For each possible category, a random sequence of 
alloca(on will be drawn for the 6 ﬁrst par(cipants that are associated to that category. 
Alloca(on will follow the sequence in the order in which par(cipants contacted the 
research team to par(cipate in the study. A list of all possible alloca(on sequences 
associated with a number has been established and a computerized random number 
generator will be used to generate the number represen(ng a sequence for each of the 
categories. AZer the 6 ﬁrst par(cipants from a category are randomized, another 
number will be generated to iden(fy the sequence used for the next series of 6 
par(cipants of that category. This will also allow for an equal number of par(cipants to 
be allocated in each group. 

 
Concealment mechanism 
This does not apply to this study, for the conduct of the study from the par(cipant’s 
point of view will be the same in both groups and that the main researcher will not be 
blinded to the alloca(on. 
 
Implementation  
The main researcher or his research assistant will be the one performing the enrolment 
of the par(cipants. However, the alloca(on to the groups will be determined by another 
researcher, that is not implicated in the recruitment. This second researcher will be the 
only person to have access to the alloca(on sequences and will assign par(cipants to the 
groups chronologically by the date at which contact was established between the 
par(cipant and the research (me, as reported by the researchers implicated in the 
recruitment and enrolment. 
 
Assignment of interventions: Blinding 
Who will be blinded 
Par(cipants will be blinded to their own alloca(on to one of the two groups. Since 
opaque eye shields are a safety requirement to perform an IPL treatment, par(cipants 
will not see the researcher apply (or not apply) the light blocker on the IPL to perform a 
sham procedure. Members of the research team that will analyse the data (grading of 
the conjunc(val scores) will also be blinded to the alloca(on of the par(cipant from 
which the data has been collected. This will be easy to ensure as the videos and images 
will be sent digitally to these members of the research team. The researcher that will 
physically perform the collect of data and the interven(ons (IPL or sham-IPL) will not be 
blinded, for this was not possible given the available resources and the safety of the IPL 
procedure. 
 
Procedure for unblinding if needed  
The only reason for which a par(cipant would be unblinded in this study is if a 
par(cipant reported persistent visual disturbance following an interven(on session (IPL 
or sham-IPL) and that BCVA was found to be decreased compared to the usual BCVA of 
the pa(ent. The alloca(on would be revealed to the par(cipant and par(cipa(on to the 
study would end. 
 
Data collection and management 
Plans for assessment and collection of outcomes  

Main data collec(on will be done at visit 1 for baseline, visit 2 and visit 5 for all 
outcomes (see par(cipant (meline, number 13) except for meibography, that will only 
be done at visit 1 and visit 5. Primary outcome (f-CLDEQ-8 ques(onnaire) will be 
assessed at every visit. The f-CLDEQ-8 has been shown to have good reliability 
(ICC=0.944) and internal consistency (Cronbach 𝛼=0.928) and to be well correlated with 
overall opinion of the contact lens66. The original CLDEQ-8 has a diagnos(c criteria of 12 
points or more and a MCID of 3 points as well as a good responsiveness68 and very good 
dose-response78 rela(onship to overall opinion of contact lens. Its use is recommended 
by the TFOS group in the Interna(onal Workshop on Contact Lens Discomfort67 as it is 
the only short and validated tool to be speciﬁc to contact lens dry eyes. This group also 
suggests that ques(oning par(cipants in clinical trial on their daily wearing (me could 
be an eﬀec(ve way of evalua(ng treatment eﬀects and that numerical global scales can 
be used to evaluate contact lens comfort67.  
TBUT using ﬂuoresceine is the standard tear stability measurement, that has been 
shown to have a sensi(vity of 72.2% and a speciﬁcity of 61.6% when a diagnos(c value 
of 10 seconds is used79. It will be established from the slit lamp through a cobalt ﬁlter 
and a handheld yellow ﬁlter to enhance visibility of the ﬂuoresceine. 3 readings will be 
taken for each eye. The measuring of NIBUT with the TFSQ func(on of the Medmont 
topographer have shown to be repeatable and to have a sensi(vity of 82% and a 
speciﬁcity of 94% for diagnosing dry eye with a cut-oﬀ of 12.1 seconds80. The validity of 
NIBUT and TFSQ over contact lens using the Medmont func(on has not been studied in 
published work; however it has been used in a RCT in 201860. 
Tear osmolarity will be measured using the i-Pen handheld osmometer. This instrument 
has been shown to be well correlated with other signs and symptoms of dry eye and to 
have a sensi(vity of 90.9% and a speciﬁcity of 90.6% to diagnose dry eye disease when a 
value of 318 mOsm/L is used as a criteria69. In vitro studies have also reported good 
repeatability and validity in determining the osmolarity of solu(ons70. The osmolarity of 
the inferior palpebral conjunc(va will be measured in this study with the par(cipants’ 
contact lenses s(ll in place. This will prevent the inﬂuence of reﬂex tearing from contact 
lens removal on osmolarity81. 
Tear volume while the contact lenses are in place will be evaluated by measuring the 
tear meniscus height using the MyAh automated func(on, which measures the height 
automa(cally in 5 diﬀerent points of the inferior meniscus. No validated study has been 
published on the measurement of this variable by the MyAh. 
To assess corneal and conjunc(val staining, sodium ﬂuoresceine and lissamine green will 
be ins(lled in the inferior fornix of the conjunc(va of each eye and picture will be taken 
through the slit lamp (with cobalt and handheld yellow ﬁlter for cornea and with no 
ﬁlter for conjunc(va) for blinded grading. The AOS system has been shown to have good 
reliability in grading anterior segment signs72 and will be used to grade corneal staining 
by running the pictures through the AOS plajorm. The Efron grading scale will be used 
for conjunc(val staining; it has been shown to have an inter-rater repeatability of 0.67 
and is a tool speciﬁc for contact lens users73. 
The degree of atrophy of the meibomian glands will be assessed by imaging the glands 
of both lids of each eye with the Lipiscan meibograph. Images will be sent for blinded 

grading using Pult’s meiboscale to determine the meiboscore (level of atrophy graded 
from 0 to 4). It is the subjec(ve grading scale that has been shown to have the best 
repeatability75, as well as high inter-rater and intra-rater reliabili(es74. 
Intra-ocular pressure will be measured using a non-contact tonometer (air puﬀ) to avoid 
ins(lling anaesthe(c drops in the par(cipants’ eyes. 
 
Plans to promote participant retention and complete follow-up 
Two strategies will be used in order to enhance par(cipants’ reten(on in the study. First, 
a courtesy call will be made to par(cipants 3 weeks aZer visit#1 to see if they are using 
the drops as required in the study, if they have concerns about the study and to 
encourage con(nuing par(cipa(on in the clinical trial. Second, ﬁnancial compensa(on 
will be given to the par(cipants for the (me that they commit to the study. Visits 1,2 and 
5 (which include complete data collec(on) will be compensated with 40$ while visits 3 
and 4 will be compensated with 20$. 
 
Data management 
A paper sheet will be used to record data that is not an image or a video (BCVA and IOP) 
and to take notes on the capture of images and videos during the collec(on of data visits 
by par(cipants. In every instrument, the nota(on will be similar and will not include the 
name or alloca(on of par(cipants (par(cipantID_V1_NIBUT_OD for instance). The sheet 
will also be used to document the treatments given. Data will be stored on password 
protected computers in the clinic (connected to secure cloud backups) and the sheets of 
paper will be kept locked at the research centre on aging of University of Sherbrooke in 
the oﬃce of the main researcher. 
 
Confidentiality  
Alpha-numerical par(cipant IDs will be assigned to the par(cipants and will be used to 
name par(cipants in every document related to the study except for the consent form, 
which will be kept in a secure and locked drawer in the oﬃce of the main researcher at 
the research centre on aging of the University of Sherbrooke. A password-secure 
document will also exist on a single computer linking the par(cipants ID to par(cipants’ 
names and will be available only to the main researcher and his research assistant. 
 
Statistical methods 
Statistical methods for primary and secondary outcomes 
Primary outcome will be the change from baseline to week 16 on the average score of 
the f-CLDEQ-8 of each group. A two-tailed t-test for independent samples will be 
conducted to evaluate sta(s(cal signiﬁcance of the diﬀerence of the change between 
the two groups. T-tests for the diﬀerence between the average score of all par(cipants 

on the f-CLDEQ-8 at baseline and the average score of all par(cipants at week 8 will also 
be conducted to evaluate the eﬀect of Cequa alone on contact lens users. 
Other measurements of par(cipants’ symptoms will generate a large number of data 
and a longitudinal analysis regression model will be used, as it is appropriate for 
repeated measures on subjects. 
Concerning the secondary outcomes, the sta(s(cal methods used will depend on the 
nature of the variable and in a way that takes in account the inter-eye correla(on of a 
given par(cipant. Con(nuous variables (f-TBUT, NIBUT, tear osmolarity, tear meniscus 
height, that will be collected on both eyes of each par(cipant, will be analysed using a 
mul(-level model. Categorical variables (Meibomian gland atrophy score, corneal 
staining score and conjunc(val staining score) will be analysed using a general linear 
model (GLM). 
 
Methods in analysis to handle protocol non-adherence and any statistical 
methods to handle missing data 
In case of dropouts of the study, consent to con(nue limited contact will be asked to 
dropout par(cipants.  The f-CLDEQ-8 will s(ll be sent to dropout par(cipants for 
comple(on at the originally scheduled data collec(on (mes to avoid missing data. 
Analysis will be made in intent-to-treat principle. Non-adherence will not be mi(gated 
by sta(s(cal methods to avoid introducing bias in the conclusions of the study. 
 
Plans to give access to the full protocol, participant level-data and 
statistical code 
Access to the full protocol and data will be available upon individual requests any (me 
aZer publica(on of the results of this clinical trial. However, in order to gain access to 
this informa(on, requesters will have to be veriﬁed scholars, clearly state the mo(ve for 
which the data is wanted and a plan to securely store the data. 
 
Oversight and monitoring 
Composition of the data monitoring committee  
A data monitoring/coordina(ng commiaee has been formed and is composed of the 
optometrist that is the owner of the clinic in which the study takes place, one 
independent clinician optometrist with a research training, one professor at another 
university (School of Optometry of University of Montreal) and one sta(s(cal expert 
from the establishment in which the study is done (University of Sherbrooke, Centre of 
Research on Aging). The commiaee will meet aZer 1/3 of the par(cipants have ﬁnished 
their implica(on in the study, aZer 2/3 of the par(cipants have ﬁnished their implica(on 
in the study and aZer data collec(on is over for all par(cipants. 
 

Adverse event reporting and harms 
Adverse events will be inventoried with a homemade ques(onnaire. Par(cipants are ﬁrst 
asked to describe on a Likert scale the intensity of their discomfort and of their blurry 
vision while ins(lling the Cequa drops. There is then an open ques(on about other side 
eﬀects that they think are linked to the Cequa eyedrop. 
The second part of the ques(onnaire asks about adverse eﬀects of IPL. Par(cipants are 
to report the presence/absence and grade (0-10 if present) the following side eﬀects: 
peri-ocular pain, eye pain, sensa(on of burning, eyelash loss, redness of the eyes, 
redness of the skin and blurry vision. Separate ques(ons concern the (me during the 
procedure, in the following 12 hours and in the following 3 weeks. An open ques(on 
also allows par(cipants to describe and grade other side eﬀects that they aaribute to 
the IPL. 
 
Plans for communicating important protocol amendments to relevant 
parties (e.g. trial participants, ethical committees) 
The ethics commiaee will be no(ﬁed by the web plajorm as soon as an amendment is 
made to the protocol and the research will pause un(l authoriza(on is given from the 
commiaee. Members of the research team that are not implicated directly in data 
collec(on will be no(ﬁed by email. 
Par(cipants will be contacted by telephone, including those who have already 
completed the study. Consent of the amended protocol will be obtained once again from 
each par(cipant with emphasis on the changes made from the original. 
 
Dissemination plans 
Poster presenta(ons and peer-reviewed publica(ons (between 1 and 4) will serve to 
communicate the results of this study with the scien(ﬁc community. Each publica(on 
will be on a speciﬁc aspect of the data and, possibly, on secondary analysis of the data. 
 
Discussion 
Some aspects of this project have, to the author’s knowledge, never been studied 
before. For instance, no data currently exist on the eﬀect of Cequa eyedrop on contact 
lens users. The combina(on of cyclosporine and IPL treatments have also never been 
studied. In the absence of a suitable comparator and given the exploratory nature of the 
objec(ve 3, it has been decided that this before-aZer comparison (with no placebo 
against Cequa) would be of interest, even though the risk of bias is stronger with such a 
study design. 
 
It has also decided that recruitment would be large in order to represent a large por(on 
of uncomfortable contact lens wearers that clinicians see in their prac(ces on a daily 
basis. Dry eye disease and contact lens discomfort being condi(ons that are, in essence, 

symptoma(c, it has been decided that recruitment would focus on symptoms rather 
than having eligibility criteria based on clinical signs or diagnos(c. 
 
The biggest prac(cal issue in this study is that it was not possible to make it double-
blind. The main researcher will also be the one collec(ng the data and performing the 
treatments. Given the nature of the IPL treatment, it was not possible to conceal from 
the researcher performing it the alloca(on of the par(cipants. However, almost all the 
data will be analysed by raters (or automa(c systems) that are not aware of the 
alloca(on of the par(cipants. 
 
Another issue is that a few eﬀects could require careful considered before drawing 
conclusions from this clinical trial. The order eﬀect, in which the order of administra(on 
of treatments inﬂuence how they are eﬀec(ve, is possible. For instance, it would be 
possible that the Cequa treatment targets some of the ac(on sites of the IPL treatment 
and already has a therapeu(c eﬀect, lessening the eﬃcacy of the IPL. Also, the dose-
response eﬀect could play a role in this study. This eﬀect, also seen in clinical prac(ce, 
concerns situa(ons in which the repeated administra(on of a treatment (resul(ng in an 
increase in dosage over (me) ampliﬁes its therapeu(c eﬀect. In the present study, the 
Cequa drop will be used twice a day for the whole 4 months. Studies on Cequa has 
shown that some signs reach their peak improvement aZer 56 days (about 2 months)76, 
while others seem to con(nue improving beyond day 5634. The improvements due to the 
cumulated dose of Cequa could be undis(nguishable from the eﬀect of IPL (and its 
cumulated dose aZer 3 treatments) in the ﬁnal data collec(on. 
 
Compliance is another issue that could arise in this study. The Cequa treatment being 
applied at home by par(cipants, it is diﬃcult to monitor thoroughly their compliance to 
it. On the other hand, the IPL treatment is applied by the research team in the clinic. 
Thus, compliance issues only apply to one of the treatments of the study. It will be 
monitored twice a week by an electronically sent ques(on asking how many doses were 
forgoaen in the past days. Although imperfect, this method lessens the burden for 
par(cipants when compared to other methods frequently used, like the gathering of 
used vials, which have also been shown to be subject to important bias82. 
 
The choice of variables to collect was also an issue while designing this study, given the 
lack of consensus on the best clinical outcomes to characterize contact lens dry eye and 
discomfort67 and what was possible to do in the context of this study. Choices were 
made to favour objec(ve outcomes that have been studies in the past and that are 
relevant to the treatments. Rapidity and comfort for the par(cipants was also taken into 
account.  
 
There are many strengths in this study. The randomiza(on of par(cipants should 
minimize bias that would arise from a diﬀerence in characteris(cs between the two 
groups. The presence of the control group will allow the research team to study the 
eﬀects of adding IPL to a contact lens wearers already taking cyclosporine drops. It will 

allow to isolate the eﬀect of IPL and to make sure that the possible improvement does 
not come from other elements (such as the psychological eﬀects of receiving treatment). 
The con(nued improvement in the condi(on that the cyclosporine drop could provide 
will be monitored due to the control group. Also, in this study, the clinicians that will 
grade the conjunc(val staining score and the meibography score will be blinded to the 
alloca(on of the par(cipants. Corneal staining will be graded by an objec(ve ar(ﬁcial 
intelligence plajorm, adding even more objec(vity and consistency to the results. The 
main outcome also is collected using the f-CLDEQ-8, a validated transla(on of the 
CLDEQ-8, which is the main ques(onnaire seen in studies to assess contact lens 
discomfort. Finally, the use of sta(s(cal methods that consider the correla(on between 
the two eyes of a given par(cipant allows for full usage of the collected data without 
increasing the risk of type I errors; it is a recommended approach in dealing with the 
inter-eye sta(s(cal challenge83. 
 
One of the limits of this study is the great number of confounding factors that exist in 
contact lens discomfort. It can be caused and inﬂuenced by many diﬀerent elements 
(material of the lens, contact lens wear history, curvature, solu(on used, modulus of the 
lens, toricity, environment, occupa(on, make-up, etc.) which could not be all accounted 
for and could inﬂuence the eﬃcacy of the treatments. The study also lacks a direct 
measurement of inﬂamma(on. MMP-9 is the marker that can be measured with 
commercial equipment; however, the cost of this machine could not be ﬁaed in the 
budget of the study. Osmolarity, however, will be measured, which has been shown to 
correlate well with MMP-9 levels84. Another limit is that the researcher that will be 
performing the treatments will not be blinded to the alloca(on. In the context of a 
treatment that has to be performed in clinic and requires some skills, it was not possible 
for this member of the research team to be blinded to the alloca(on. Finally, a limit 
resides in the fact that the main outcome is based on subjec(ve impressions of the 
par(cipants. Bias of social desirability or enthusiasm of the par(cipants could impact the 
measured change in symptoms. 
  
Trial status 
A pilot study was conducted in the fall of 2023 and recruitment for the oﬃcial RCT 
should start in April 2024. Version #3 of the protocol (February 2024) is the protocol that 
is currently being used. Recruitment is expected to ﬁnish in October or November of 
2025. 
 
Abbrevia1ons 
 
MGD: Meibomian Gland Dysfunc(on 
IPL: Intense Pulsed Light 
TBUT: Tear Break-Up Time 
NIBUT: Non-Invasive Break-Up Time 

f-TBUT: Tear Break-Up Time measured using sodium ﬂuoresceine 
f-CLDEQ-8: French version of the Contact Lens Dry Eye Ques(onnaire-8 
TMH: Tear Meniscus Height 
SCL: SoZ Contact Lens 
BCVA: Best Corrected Visual Acuity 
IOP: Intra-Ocular Pressure 
MCID: Minimal Clinically Important Diﬀerence 
TFOS: Tear Film Ocular Society 
GLM: General Linear Model 
RCT: Randomized Clinical Trial 
TFSQ: Tear Film Surface Quality 
 
Declarations 
Funding 
This study has three sources of funding. First, part of it will be auto-funded by the 
researchers’ personal funds. Secondly, the Canadian Optometric Trust Fund (COETF) gave 
a 1500$ award in 2021 to help fund the project. Thirdly, and most importantly, the 
project is funded through a MITACS grant (15,000$). This was made possible by the 
contribu(on of half of this amount by Sun Pharma. The company also provides the 
Cequa drops used during the study free of charge. 
 
Ethics approval and consent to par7cipate 
This project has been approved by the Comité d’éthique à la recherche du CIUSSS de 
l’Estrie-CHUS (project number 2024-5200). All material related to the project, including 
consent forms, ques(onnaires, recruitment documents, funding, and scien(ﬁc relevance 
have been reviewed and approved by this commiaee. 
 
Par(cipants will be given an informa(on and consent form that is wriaen in simple 
language. This document, available in English and in French, will be given to the 
par(cipants by email before planning visit#1 to give them (me to review the 
informa(on. The research team will be available by email or telephone if the 
par(cipants have any ques(ons. Consent to par(cipate will be renewed before each 
treatment and par(cipants will be free to withdraw at any moment without jus(ﬁca(on. 
 
References 
 
1. 
Craig JP, Nichols KK, Akpek EK, Caﬀery B, Dua HS, Joo CK, et al. TFOS DEWS II 
Deﬁni(on and Classiﬁca(on Report. Ocul Surf. 2017;15(3):276-83. 
2. 
Papas EB. The global prevalence of dry eye disease: A Bayesian view. Ophthalmic 
Physiol Opt. 2021;41(6):1254-66. 

3. 
Stapleton F, Alves M, Bunya VY, Jalbert I, Lekhanont K, Malet F, et al. TFOS DEWS 
II Epidemiology Report. Ocul Surf. 2017;15(3):334-65. 
4. 
Rouen PA, White ML. Dry Eye Disease: Prevalence, Assessment, and 
Management. Home Healthc Now. 2018;36(2):74-83. 
5. 
Chhadva P, Goldhardt R, Galor A. Meibomian Gland Disease: The Role of Gland 
Dysfunc(on in Dry Eye Disease. Ophthalmology. 2017;124(11S):S20-S6. 
6. 
Hassanzadeh S, Varmaghani M, Zarei-Ghanava( S, Heravian Shandiz J, Azimi 
Khorasani A. Global Prevalence of Meibomian Gland Dysfunc(on: A Systema(c Review 
and Meta-Analysis. Ocul Immunol Inﬂamm. 2021;29(1):66-75. 
7. 
Schaumberg DA, Nichols JJ, Papas EB, Tong L, Uchino M, Nichols KK. The 
interna(onal workshop on meibomian gland dysfunc(on: report of the subcommiaee 
on the epidemiology of, and associated risk factors for, MGD. Invest Ophthalmol Vis Sci. 
2011;52(4):1994-2005. 
8. 
Gomes JAP, Azar DT, Baudouin C, Efron N, Hirayama M, Horwath-Winter J, et al. 
TFOS DEWS II iatrogenic report. Ocul Surf. 2017;15(3):511-38. 
9. 
Dumbleton K, Caﬀery B, Dogru M, Hickson-Curran S, Kern J, Kojima T, et al. The 
TFOS Interna(onal Workshop on Contact Lens Discomfort: report of the subcommiaee 
on epidemiology. Invest Ophthalmol Vis Sci. 2013;54(11):TFOS20-36. 
10. 
Koh S. Contact Lens Wear and Dry Eye: Beyond the Known. Asia Pac J Ophthalmol 
(Phila). 2020;9(6):498-504. 
11. 
Chalmers RL, Young G, Kern J, Napier L, Hunt C. SoZ Contact Lens-Related 
Symptoms in North America and the United Kingdom. Optom Vis Sci. 2016;93(8):836-47. 
12. 
Sulley A, Young G, Hunt C, McCready S, Targea MT, Craven R. Reten(on Rates in 
New Contact Lens Wearers. Eye Contact Lens. 2018;44 Suppl 1:S273-S82. 
13. 
Willcox MDP, Argueso P, Georgiev GA, Holopainen JM, Laurie GW, Millar TJ, et al. 
TFOS DEWS II Tear Film Report. Ocul Surf. 2017;15(3):366-403. 
14. 
Bron AJ, de Paiva CS, Chauhan SK, Bonini S, Gabison EE, Jain S, et al. TFOS DEWS II 
pathophysiology report. Ocul Surf. 2017;15(3):438-510. 
15. 
Guillon M, Maissa C. Contact lens wear aﬀects tear ﬁlm evapora(on. Eye Contact 
Lens. 2008;34(6):326-30. 
16. 
Nichols JJ, Sinnoa LT. Tear ﬁlm, contact lens, and pa(ent-related factors 
associated with contact lens-related dry eye. Invest Ophthalmol Vis Sci. 
2006;47(4):1319-28. 
17. 
Alghamdi WM, Markoulli M, Holden BA, Papas EB. Impact of dura(on of contact 
lens wear on the structure and func(on of the meibomian glands. Ophthalmic Physiol 
Opt. 2016;36(2):120-31. 
18. 
Ucakhan O, Arslanturk-Eren M. The Role of SoZ Contact Lens Wear on 
Meibomian Gland Morphology and Func(on. Eye Contact Lens. 2019;45(5):292-300. 
19. 
Insua Pereira E, Sampaio AP, Lira M. Eﬀects of contact lens wear on tear 
inﬂammatory biomarkers. Cont Lens Anterior Eye. 2022;45(5):101600. 
20. 
Alzahrani Y, Colorado LH, Pritchard N, Efron N. Longitudinal changes in 
Langerhans cell density of the cornea and conjunc(va in contact lens-induced dry eye. 
Clin Exp Optom. 2017;100(1):33-40. 

21. 
Efron N. Contact lens wear is intrinsically inﬂammatory. Clin Exp Optom. 
2017;100(1):3-19. 
22. 
Periman LM, Mah FS, Karpecki PM. A Review of the Mechanism of Ac(on of 
Cyclosporine A: The Role of Cyclosporine A in Dry Eye Disease and Recent Formula(on 
Developments. Clin Ophthalmol. 2020;14:4187-200. 
23. 
Wan KH, Chen LJ, Young AL. Eﬃcacy and Safety of Topical 0.05% Cyclosporine Eye 
Drops in the Treatment of Dry Eye Syndrome: A Systema(c Review and Meta-analysis. 
Ocul Surf. 2015;13(3):213-25. 
24. 
Rao SN. Topical cyclosporine 0.05% for the preven(on of dry eye disease 
progression. J Ocul Pharmacol Ther. 2010;26(2):157-64. 
25. 
Chen M, Gong L, Sun X, Xie H, Zhang Y, Zou L, et al. A comparison of cyclosporine 
0.05% ophthalmic emulsion versus vehicle in Chinese pa(ents with moderate to severe 
dry eye disease: an eight-week, mul(center, randomized, double-blind, parallel-group 
trial. J Ocul Pharmacol Ther. 2010;26(4):361-6. 
26. 
Prabhasawat P, Tesavibul N, Mahawong W. A randomized double-masked study of 
0.05% cyclosporine ophthalmic emulsion in the treatment of meibomian gland 
dysfunc(on. Cornea. 2012;31(12):1386-93. 
27. 
Chen D, Zhang S, Bian A, Hong J, Deng Y, Zhang M, et al. Eﬃcacy and safety of 
0.05% cyclosporine ophthalmic emulsion in treatment of Chinese pa(ents with 
moderate to severe dry eye disease: A 12-week, mul(center, randomized, double-
masked, placebo-controlled phase III clinical study. Medicine (Bal(more). 
2019;98(31):e16710. 
28. 
Hom MM. Use of cyclosporine 0.05% ophthalmic emulsion for contact lens-
intolerant pa(ents. Eye Contact Lens. 2006;32(2):109-11. 
29. 
Willen CM, McGwin G, Liu B, Owsley C, Rosens(el C. Eﬃcacy of cyclosporine 
0.05% ophthalmic emulsion in contact lens wearers with dry eyes. Eye Contact Lens. 
2008;34(1):43-5. 
30. 
Wang L, Chen X, Hao J, Yang L. Proper balance of omega-3 and omega-6 faay acid 
supplements with topical cyclosporine aaenuated contact lens-related dry eye 
syndrome. Inﬂammopharmacology. 2016;24(6):389-96. 
31. 
Jerkins GW, Paaar GR, Kannarr SR. A Review of Topical Cyclosporine A 
Formula(ons-A Disease-Modifying Agent for Keratoconjunc(vi(s Sicca. Clin Ophthalmol. 
2020;14:481-9. 
32. 
Mandal A, Gote V, Pal D, Ogundele A, Mitra AK. Ocular Pharmacokine(cs of a 
Topical Ophthalmic Nanomicellar Solu(on of Cyclosporine (Cequa(R)) for Dry Eye 
Disease. Pharm Res. 2019;36(2):36. 
33. 
Weiss SL, Kramer WG. Ocular Distribu(on of Cyclosporine Following Topical 
Administra(on of OTX-101 in New Zealand White Rabbits. J Ocul Pharmacol Ther. 
2019;35(7):395-402. 
34. 
Malhotra R, Devries DK, Luchs J, Kabat A, Schechter BA, Shen Lee B, et al. Eﬀect of 
OTX-101, a Novel Nanomicellar Formula(on of Cyclosporine A, on Corneal Staining in 
Pa(ents With Keratoconjunc(vi(s Sicca: A Pooled Analysis of Phase 2b/3 and Phase 3 
Studies. Cornea. 2019;38(10):1259-65. 

35. 
Smyth-Medina R, Johnston J, Devries DK, Jasper A, Kannarr SR, Schechter BA, et 
al. Eﬀect of OTX-101, a Novel Nanomicellar Formula(on of Cyclosporine A, on 
Conjunc(val Staining in Pa(ents with Keratoconjunc(vi(s Sicca: A Pooled Analysis of 
Phase 2b/3 and 3 Clinical Trials. J Ocul Pharmacol Ther. 2019;35(7):388-94. 
36. 
Sheppard J, Kannarr S, Luchs J, Malhotra R, Jus(ce A, Ogundele A, et al. Eﬃcacy 
and Safety of OTX-101, a Novel Nanomicellar Formula(on of Cyclosporine A, for the 
Treatment of Keratoconjunc(vi(s Sicca: Pooled Analysis of a Phase 2b/3 and Phase 3 
Study. Eye Contact Lens. 2020;46 Suppl 1:S14-S9. 
37. 
Toyos M, Gupta PK, Mitchell B, Karpecki P. The Eﬀect of OTX-101 on Tear 
Produc(on in Pa(ents with Severe Tear-deﬁcient Dry Eye Disease: A Pooled Analysis of 
Phase 2b/3 and Phase 3 Studies. Curr Eye Res. 2022;47(2):220-4. 
38. 
Sheppard J, Bergmann M, Schechter BA, Luchs J, Ogundele A, Karpecki P. Phase 3 
Eﬃcacy (Worse-Eye Analysis) and Long-Term Safety Evalua(on of OTX-101 in Pa(ents 
with Keratoconjunc(vi(s Sicca. Clin Ophthalmol. 2021;15:129-40. 
39. 
Raulin C, Greve B, Grema H. IPL technology: a review. Lasers Surg Med. 
2003;32(2):78-87. 
40. 
Rennick S, Adcock L.  Intense Pulsed Light Therapy for Meibomian Gland 
Dysfunc(on: A Review of Clinical Eﬀec(veness and Guidelines. CADTH Rapid Response 
Reports. Oaawa (ON)2018. 
41. 
Dell SJ. Intense pulsed light for evapora(ve dry eye disease. Clin Ophthalmol. 
2017;11:1167-73. 
42. 
Giannaccare G, Taroni L, Senni C, Scorcia V. Intense Pulsed Light Therapy In The 
Treatment Of Meibomian Gland Dysfunc(on: Current Perspec(ves. Clin Optom (Auckl). 
2019;11:113-26. 
43. 
Suwal A, Hao JL, Zhou DD, Liu XF, Suwal R, Lu CW. Use of Intense Pulsed Light to 
Mi(gate Meibomian Gland Dysfunc(on for Dry Eye Disease. Int J Med Sci. 
2020;17(10):1385-92. 
44. 
Craig JP, Chen YH, Turnbull PR. Prospec(ve trial of intense pulsed light for the 
treatment of meibomian gland dysfunc(on. Invest Ophthalmol Vis Sci. 2015;56(3):1965-
70. 
45. 
Piyacomn Y, Kasetsuwan N, Reinprayoon U, Sa(tpitakul V, Tesapirat L. Eﬃcacy and 
Safety of Intense Pulsed Light in Pa(ents With Meibomian Gland Dysfunc(on-A 
Randomized, Double-Masked, Sham-Controlled Clinical Trial. Cornea. 2020;39(3):325-32. 
46. 
Xue AL, Wang MTM, Ormonde SE, Craig JP. Randomised double-masked placebo-
controlled trial of the cumula(ve treatment eﬃcacy proﬁle of intense pulsed light 
therapy for meibomian gland dysfunc(on. Ocul Surf. 2020;18(2):286-97. 
47. 
Toyos R, Desai NR, Toyos M, Dell SJ. Intense pulsed light improves signs and 
symptoms of dry eye disease due to meibomian gland dysfunc(on: A randomized 
controlled study. PLoS One. 2022;17(6):e0270268. 
48. 
Miao S, Yan R, Jia Y, Pan Z. Eﬀect of Intense Pulsed Light Therapy in Dry Eye 
Disease Caused by Meibomian Gland Dysfunc(on: A Systema(c Review and Meta-
Analysis. Eye Contact Lens. 2022;48(10):424-9. 
49. 
Vegunta S, Patel D, Shen JF. Combina(on Therapy of Intense Pulsed Light Therapy 
and Meibomian Gland Expression (IPL/MGX) Can Improve Dry Eye Symptoms and 

Meibomian Gland Func(on in Pa(ents With Refractory Dry Eye: A Retrospec(ve 
Analysis. Cornea. 2016;35(3):318-22. 
50. 
Sambhi RS, Sambhi GDS, Mather R, Malvankar-Mehta MS. Intense pulsed light 
therapy with meibomian gland expression for dry eye disease. Can J Ophthalmol. 
2020;55(3):189-98. 
51. 
Arita R, Fukuoka S, Morishige N. Therapeu(c eﬃcacy of intense pulsed light in 
pa(ents with refractory meibomian gland dysfunc(on. Ocul Surf. 2019;17(1):104-10. 
52. 
Rong B, Tang Y, Tu P, Liu R, Qiao J, Song W, et al. Intense Pulsed Light Applied 
Directly on Eyelids Combined with Meibomian Gland Expression to Treat Meibomian 
Gland Dysfunc(on. Photomed Laser Surg. 2018;36(6):326-32. 
53. 
Shin KY, Lim DH, Moon CH, Kim BJ, Chung TY. Intense pulsed light plus meibomian 
gland expression versus intense pulsed light alone for meibomian gland dysfunc(on: A 
randomized crossover study. PLoS One. 2021;16(3):e0246245. 
54. 
Yang L, Pazo EE, Zhang Q, Wu Y, Song Y, Qin G, et al. Treatment of contact lens 
related dry eye with intense pulsed light. Cont Lens Anterior Eye. 2022;45(2):101449. 
55. 
Xu L, Wu Y, Song Y, Zhang Q, Qin G, Yang L, et al. Comparison Between Heated 
Eye Mask and Intense Pulsed Light Treatment for Contact Lens-Related Dry Eye. 
Photobiomodul Photomed Laser Surg. 2022;40(3):189-97. 
56. 
Yan S, Wu Y. Eﬃcacy and safety of Intense pulsed light therapy for dry eye caused 
by meibomian gland dysfunc(on: a randomised trial. Ann Palliat Med. 2021;10(7):7857-
65. 
57. 
Hovanesian JA, Berdy GJ, Epitropoulos A, Holladay JT. Eﬀect of Cyclosporine 
0.09% Treatment on Accuracy of Preopera(ve Biometry and Higher Order Aberra(ons in 
Dry Eye Pa(ents Undergoing Cataract Surgery. Clin Ophthalmol. 2021;15:3679-86. 
58. 
Shen Lee B, Toyos M, Karpecki P, Schizauer J, Sheppard J. Selec(ve 
Pharmacologic Therapies for Dry Eye Disease Treatment: Eﬃcacy, Tolerability, and Safety 
Data Review from Preclinical Studies and Pivotal Trials. Ophthalmol Ther. 
2022;11(4):1333-69. 
59. 
Efron N, Jones L, Bron AJ, Knop E, Arita R, Barabino S, et al. The TFOS 
Interna(onal Workshop on Contact Lens Discomfort: report of the contact lens 
interac(ons with the ocular surface and adnexa subcommiaee. Invest Ophthalmol Vis 
Sci. 2013;54(11):TFOS98-TFOS122. 
60. 
Downie LE, Gad A, Wong CY, Gray JHV, Zeng W, Jackson DC, et al. Modula(ng 
Contact Lens Discomfort With An(-Inﬂammatory Approaches: A Randomized Controlled 
Trial. Invest Ophthalmol Vis Sci. 2018;59(8):3755-66. 
61. 
Fernandez I, Lopez-Miguel A, Mar(n-Montanez V, Enriquez-de-Salamanca A, 
Calonge M, Gonzalez-Meijome JM, et al. Inﬂammatory status predicts contact lens 
discomfort under adverse environmental condi(ons. Ocul Surf. 2020;18(4):829-40. 
62. 
Toyos R, McGill W, Briscoe D. Intense pulsed light treatment for dry eye disease 
due to meibomian gland dysfunc(on; a 3-year retrospec(ve study. Photomed Laser Surg. 
2015;33(1):41-6. 
63. 
Gupta PK, Vora GK, Matossian C, Kim M, S(nnea S. Outcomes of intense pulsed 
light therapy for treatment of evapora(ve dry eye disease. Can J Ophthalmol. 
2016;51(4):249-53. 

64. 
Yuraaser Ocak S, Karakus S, Ocak OB, Cakir A, Bolukbasi S, Erden B, et al. Intense 
pulse light therapy treatment for refractory dry eye disease due to meibomian gland 
dysfunc(on. Int Ophthalmol. 2020;40(5):1135-41. 
65. 
Vigo L, Taroni L, Bernabei F, Pellegrini M, Sebas(ani S, Mercan( A, et al. Ocular 
Surface Workup in Pa(ents with Meibomian Gland Dysfunc(on Treated with Intense 
Regulated Pulsed Light. Diagnos(cs (Basel). 2019;9(4). 
66. 
Lor(e-Milner E, Boily L, Michaud L, Quesnel NM, Simard P, Milner V, et al. 
Transla(on and valida(on of the contact lens dry eye ques(onnaire 8 (CLDEQ-8) in 
Canadian French. Cont Lens Anterior Eye. 2023;46(2):101779. 
67. 
Foulks G, Chalmers R, Keir N, Woods CA, Simpson T, Lippman R, et al. The TFOS 
Interna(onal Workshop on Contact Lens Discomfort: report of the subcommiaee on 
clinical trial design and outcomes. Invest Ophthalmol Vis Sci. 2013;54(11):TFOS157-83. 
68. 
Chalmers RL, Keay L, Hickson-Curran SB, Gleason WJ. Cutoﬀ score and 
responsiveness of the 8-item Contact Lens Dry Eye Ques(onnaire (CLDEQ-8) in a Large 
daily disposable contact lens registry. Cont Lens Anterior Eye. 2016;39(5):342-52. 
69. 
Park J, Choi Y, Han G, Shin E, Han J, Chung TY, et al. Evalua(on of tear osmolarity 
measured by I-Pen osmolarity system in pa(ents with dry eye. Sci Rep. 2021;11(1):7726. 
70. 
Chan CC, Borovik A, Hofmann I, Gulliver E, Rocha G. Validity and Reliability of a 
Novel Handheld Osmolarity System for Measurement of a Na(onal Ins(tute of 
Standards Traceable Solu(on. Cornea. 2018;37(9):1169-74. 
71. 
Chen Q, Wang J, Shen M, Cui L, Cai C, Li M, et al. Tear menisci and ocular 
discomfort during daily contact lens wear in symptoma(c wearers. Invest Ophthalmol 
Vis Sci. 2011;52(5):2175-80. 
72. 
Walker MK, Tomiyama ES, Skidmore KV, Assaad JR, Ticak A, Richdale K. A 
comparison of subjec(ve and objec(ve conjunc(val hyperaemia grading with AOS(R) 
Anterior soZware. Clin Exp Optom. 2022;105(5):494-9. 
73. 
Efron N, Morgan PB, Katsara SS. Valida(on of grading scales for contact lens 
complica(ons. Ophthalmic Physiol Opt. 2001;21(1):17-29. 
74. 
Pult H, Riede-Pult B. Comparison of subjec(ve grading and objec(ve assessment 
in meibography. Cont Lens Anterior Eye. 2013;36(1):22-7. 
75. 
Bino^ WW, Bayraktutar B, Ozmen MC, Cox SM, Hamrah P. A Review of Imaging 
Biomarkers of the Ocular Surface. Eye Contact Lens. 2020;46 Suppl 2(Suppl 2):S84-S105. 
76. 
Tauber J, Schechter BA, Bacharach J, Toyos MM, Smyth-Medina R, Weiss SL, et al. 
A Phase II/III, randomized, double-masked, vehicle-controlled, dose-ranging study of the 
safety and eﬃcacy of OTX-101 in the treatment of dry eye disease. Clin Ophthalmol. 
2018;12:1921-9. 
77. 
Tang Y, Liu R, Tu P, Song W, Qiao J, Yan X, et al. A Retrospec(ve Study of 
Treatment Outcomes and Prognos(c Factors of Intense Pulsed Light Therapy Combined 
With Meibomian Gland Expression in Pa(ents With Meibomian Gland Dysfunc(on. Eye 
Contact Lens. 2021;47(1):38-44. 
78. 
Chalmers RL, Begley CG, Moody K, Hickson-Curran SB. Contact Lens Dry Eye 
Ques(onnaire-8 (CLDEQ-8) and opinion of contact lens performance. Optom Vis Sci. 
2012;89(10):1435-42. 

79. 
Methodologies to diagnose and monitor dry eye disease: report of the Diagnos(c 
Methodology Subcommiaee of the Interna(onal Dry Eye WorkShop (2007). Ocul Surf. 
2007;5(2):108-52. 
80. 
Downie LE. Automated Tear Film Surface Quality Breakup Time as a Novel Clinical 
Marker for Tear Hyperosmolarity in Dry Eye Disease. Invest Ophthalmol Vis Sci. 
2015;56(12):7260-8. 
81. 
Gad A, Vingrys AJ, Wong CY, Jackson DC, Downie LE. Tear ﬁlm inﬂammatory 
cytokine upregula(on in contact lens discomfort. Ocul Surf. 2019;17(1):89-97. 
82. 
Vrijens B, Urquhart J. Methods for measuring, enhancing, and accoun(ng for 
medica(on adherence in clinical trials. Clin Pharmacol Ther. 2014;95(6):617-26. 
83. 
Armstrong RA. Sta(s(cal guidelines for the analysis of data obtained from one or 
both eyes. Ophthalmic Physiol Opt. 2013;33(1):7-14. 
84. 
Schargus M, Ivanova S, Kakkassery V, Dick HB, Joachim S. Correla(on of Tear Film 
Osmolarity and 2 Diﬀerent MMP-9 Tests With Common Dry Eye Tests in a Cohort of Non-
Dry Eye Pa(ents. Cornea. 2015;34(7):739-44.