Combination of 0.09% cyclosporine and intense pulsed light (IPL) therapy for the treatment of dry eye disease in symptomatic contact lens wearers: study protocol for a sham-controlled randomized clinical trial

Abstract

Background

Discomfort while using soft contact lenses is a major concern in eyecare, and it is strongly linked to dry eye. Many new dry eye therapies have not yet been studied on contact lens users. Cyclosporine is a pharmaceutical agent that has recently been re-engineered in a nanomicellar drop. Intense pulsed light is a potent treatment for meibomian gland dysfunction. Very little data exists on the effects of these treatments, and they have never been tested in combination. The aim of this study was to test the effects of the combination of nanomicellar cyclosporine and intense pulsed light on the symptoms and signs of soft contact lens users.

Methods

Forty-four symptomatic soft contact lens users will be recruited from a primary care optometry practice. They will receive cyclosporine 0.09% to use twice daily, and, after 8 weeks, they will be randomized to receive three sessions of intense pulsed light or a sham. Primary outcome will be the symptom score using a questionnaire, and secondary outcomes will include tear film stability measurements (both on the tear film and over contact lenses), tear meniscus height, osmolarity, meibomian gland atrophy, and ocular surface staining. Safety will be assessed by measuring visual acuity, intra-ocular pressure, and an adverse effects questionnaire. Questionnaire scores will be compared using a t-test, while other measurements will be analyzed using mixed-model effects.

Discussion

This study aims to test whether a combination of novel dry eye treatments that target the whole tear film improves comfort while wearing contact lenses. Discomfort is a major issue that leads to drop out. The results of this study could provide eyecare professionals with additional tools to help their patients and could open the discussion on future solutions to improve contact lens users’ experience.

Trial registration

ClinicalTrials.gov NCT06392438, registered on April 23rd, 2024.

Supplementary Information

The online version contains supplementary material available at 10.1186/s13063-026-09521-w.

Introduction

Background and rationale {6a}

Dry eye disease (DED) is a multifactorial condition characterized by tear film instability and hyperosmolarity, leading to ocular surface inflammation and damage [1]. While the estimated global prevalence is 11.6% [2], some studies suggest underdiagnosis, with up to 50% of individuals reporting symptoms consistent with DED [3]. The disease has classically been conceived as having an evaporative and an aqueous component [4]. Meibomian gland dysfunction (MGD) is a primary contributor to evaporative DED, affecting 21–30% of African and Caucasian populations and showing even higher prevalence among Arab, Hispanic, and Asian populations [5–7]. Risk factors include aging and contact lens wear [8].

Approximately 20% of the population uses soft contact lenses to correct refractive errors [9]. However, lens wear can disrupt tear film homeostasis and promote inflammation, contributing to a form of dry eye referred to as contact lens–induced dryness (CLID) [10]. Loss of goblet cells resulting from contact lens wear has also been shown to be strongly related to corneal dendritic cell density increase and symptoms [11]. Despite advances in lens materials and care products, CLID remains common, with up to 39% of North American contact lens users reporting symptoms [12]. CLID contributes to both components of DED; it is associated with reduced tear volume, tear film instability, and changes in the ocular surface and meibomian glands [13–19].

Topical cyclosporine A, an immunomodulatory agent that inhibits T-cell activation, has been used for DED management since the early 2000s [20, 21]. It increases tear production, goblet cell density, and improves clinical signs and symptoms [22–25]. While results in contact lens users are mixed [26, 27], some evidence suggests enhanced efficacy when combined with essential fatty acid supplementation [28]. A newer 0.09% nanomicellar cyclosporine formulation offers improved ocular tissue penetration and has demonstrated safety and efficacy in increasing tear volume and reducing staining [29–35].

Intense pulsed light (IPL), a therapy adapted from dermatology, has shown promise in treating MGD through mechanisms such as meibum melting, vascular ablation, photobiomodulation, and antimicrobial effects [36–38]. IPL has demonstrated improvements in tear film stability, gland secretion, and symptom relief [38–43]. Although typically combined with meibomian gland expression, IPL alone appears to be the primary driver of these therapeutic effects [44–46]. Its safety profile is favorable, with only mild and transient adverse events reported [38, 47]. Limited data suggest IPL may also benefit contact lens wearers [48, 49].

To date, no study has evaluated the combined effect of IPL and topical cyclosporine in managing CLID. The present trial is designed to assess the efficacy and safety of this combined intervention in contact lens wearers with dry eye symptoms.

Objectives {7}

The primary objective of this RCT is to assess whether combining 0.09% cyclosporine nanomicellar eye drops (16 weeks) with three IPL sessions is more effective than cyclosporine with sham IPL in reducing symptoms of dry eye in soft contact lens wearers. Secondary objectives are to compare the same treatments on clinical signs of dry eye, including TBUT, NIBUT, tear osmolarity, tear meniscus height, meibomian gland atrophy, and ocular surface staining. A third objective is to explore the effect of cyclosporine 0.09% alone on symptoms and signs in this population. The fourth objective is to evaluate the safety profile of both treatments in soft contact lens wearers.

Trial design {8}

This study is a sham-controlled, randomized, pre-post interventional superiority trial. Participants will be randomly assigned in a 1:1 ratio to one of two equal-sized groups based on the IPL intervention. The trial is registered on clinicaltrial.gov (NCT06392438).

Methods

Study setting {9}

Participant will be recruited from a network of private optometry clinics regrouped under the name Opto-réseau in Québec, Canada. The clinical portion of the study will be conducted at the Opto-réseau clinic in Sherbrooke, Canada. Data storage and analysis will be performed at the Research Center on Aging, CIUSSS Estrie CHUS, a collaborating university research center.

Eligibility criteria {10}

Inclusion criteria

Participants must meet all of the following:

• Aged 18 years or older and able to provide informed consent

• Silicone hydrogel soft contact lens wearers for at least 2 years (minimum wear of 1 day/week for 4 h)

• Use of monthly, bi-monthly, or daily disposable lenses

• Symptomatic lens wearers with an f-CLDEQ-8 score ≥ 12

Exclusion criteria

Participants will be excluded if they meet any of the following:

• Current or past use of topical 0.09% cyclosporine within the past 6 months

• Known intolerance to cyclosporine or any product used in the study

• Pregnancy or breastfeeding

• Contraindications to IPL or cyclosporine, including:

  • ◦ History of ocular HSV infection or active ocular infection
  • ◦ Photosensitizing medications, epilepsy
  • ◦ History of skin cancer, pigmented lesions, keloids, tattoos, or vitiligo in the treatment area

• Refractive surgery within the past 12 months

• Thermal pulsation treatment for MGD in the past 12 months

• Use of topical ocular medications

• Continuous contact lens wear (overnight use)

• Poor contact lens fit (excessive movement or decentration)

• Presence of giant papillary conjunctivitis

• Inability to attend all scheduled study visits

Who will take informed consent? {26a}

Informed consent will be obtained by one of the principal investigators.

Additional consent provisions for collection and use of participant data and biological specimens {26b}

N/A. No biological specimens will be collected.

Intervention

Explanation for the choice of comparators {6b}

A sham IPL procedure will be implemented to maintain blinding and control for placebo effects. To achieve this, a custom-designed light-blocking device was fabricated using 3D printing. The device consists of a hardened plastic shield that fully covers the IPL handpiece prism, preventing therapeutic light energy from reaching the participant’s skin. A 5 mm gap between the prism and the plastic blocker, along with lateral openings, allows light to escape sideways. This design minimizes internal reflection that could damage the IPL device and ensures participants perceive flashes of light through their protective eye shields, closely mimicking the visual and auditory experience of active IPL treatment. Participants wear opaque ocular shields throughout the procedure, rendering the blocking device visually undetectable. Figure 1 presents the custom light-blocking apparatus.

Fig. 1.

Picture of the IPL filter over the M22 Lumenis prism

Intervention description {11a}

Participants will self-administer 0.09% cyclosporine eye drops twice daily in both eyes for 16 weeks, using separate single-dose vials for morning and evening. They will be instructed to wait 15 min after instilling drops before inserting contact lenses, and to wait 15 min after lens removal before instilling drops. The second intervention, for the experimental group, is a standard IPL procedure as described by Toyos [50]. Participants in the experimental group will receive IPL treatment for both eyes (those in the sham group will receive the sham IPL treatment for both eyes). For the IPL procedure, opaque eye shields will be placed over the closed eyelids, and IPL gel applied from temple to temple, including the nasal bridge and just below the lower lid. The IPL device will be set with a 590 nm filter, contact cooling, and three pulses per shot (6–50 ms pulse-pause cycles). Fluence will be adjusted based on Fitzpatrick skin type (e.g., 16 J/cm² for type I, 13 J/cm² for type IV). A total of 30 overlapping IPL shots (15 per pass across the treatment area spanning equally around both eyes) will be delivered in two full passes. Figure 2 illustrates the treatment pattern.

Fig. 2.

Half of one passage of IPL treatment plan

Criteria for discontinuing or modifying allocated interventions {11b}

Either intervention will be discontinued if a serious adverse event (SAE) occurs. For this study, an SAE is defined as any event potentially related to the intervention that requires medical management (e.g., prescription of anti-inflammatory or antimicrobial agents, surgical intervention) and/or poses a risk of long-term visual impairment. Mild discomfort from cyclosporine drops or IPL is anticipated and will not warrant discontinuation. Participant withdrawal from the study at any time will also result in cessation of the assigned treatment. Under no circumstances will participants be reassigned to the other study group.

Strategies to improve adherence to interventions {11c}

Non-adherence is a potential concern for the cyclosporine intervention, given its self-administered nature. To promote compliance, participants will receive a follow-up telephone call from the research team three weeks after treatment initiation. Additionally, weekly text message prompts will be sent to inquire about recent drop usage, serving both as a self-monitoring tool and adherence reminder. Adherence to the IPL intervention is not anticipated to be problematic, as it is administered in-clinic under direct supervision and requires minimal time.

Relevant concomitant care permitted or prohibited during the trial {11d}

Since participants will be compared statistically to themselves, and that these treatments and their effects can vary between individuals, participants will be allowed to maintain their existing dry eye treatments, provided these do not conflict with the exclusion criteria. Permitted concurrent therapies include artificial tears, lubricating ointments, omega-3 supplementation, warm compresses, eyelid hygiene, and punctal plugs. However, the initiation of any new dry eye therapies during the 4-month study period will not be permitted, in order to avoid confounding treatment effects.

Provisions for post-trial care {30}

Participants will be recruited from a private optometric clinic where the study is conducted. Following study completion, participants may continue their dry eye management at any clinic offering appropriate services, including the study site.

Outcomes {12}

The primary outcome of this study is the evaluation of dry eye symptoms during contact lens wear, assessed using the French version of the Contact Lens Dry Eye Questionnaire-8 (f-CLDEQ-8), a validated instrument [51]. The CLDEQ-8 is recommended by the Tear Film and Ocular Surface Society (TFOS) for assessing symptoms related to contact lens discomfort [52]. Scores will be collected at each study visit, with the primary analysis focusing on the change from baseline to 16 weeks. The mean change in symptom scores will be calculated for each group and compared between groups. A clinically important difference (CID) for the CLDEQ-8 has been established at 3 points [53], supporting its responsiveness in detecting meaningful changes in contact lens comfort. In addition, participants will receive biweekly electronic questionnaires assessing contact lens comfort using a 0–100 scale. This global rating scale, also endorsed by TFOS, provides a continuous measure of perceived comfort [52]. These messages will also include questions regarding average daily contact lens wearing time and artificial tear use over the preceding 3–4 days, serving as indirect indicators of contact lens-related discomfort.

Secondary outcomes

1. Tear film stability over contact lenses

   Assessed using the Medmont E300’s TFSQ and NIBUT functions with contact lenses in place. The mean of three measurements per eye will be recorded. Normal NIBUT over lenses is typically 6–8 s [54].

• 2.Tear film osmolarity

  Measured with the i-Pen osmometer at the inferior lid margin of each eye. Values <308 mOsm/L are considered normal, while >315 mOsm/L are indicative of dry eye [55–57].

• 3.Tear volume

  Evaluated via tear meniscus height using the Myah (Topcon) with contact lenses in place [58]. Measurements will be taken 1–2 s after two blinks and averaged across five points. Normal range is 0.20–0.24 mm [59, 60].

• 4.Tear film stability (without contact lenses)

  Measured 15 min post lens removal using:

  • ◦ Medmont E300 (TFSQ/NIBUT): TFSQ values < 12.1 s are considered normal [61].
  • ◦ Fluorescein TBUT: Recorded via slit lamp with cobalt and yellow filters, 30 s post fluorescein instillation. Mean of three trials used. TBUT < 10 s indicates instability [62].
• 5.Corneal and conjunctival staining

  Corneal staining (fluorescein) and conjunctival staining (lissamine green) will be documented via slit lamp imaging. Corneal images will be analyzed using AOS software; conjunctival images will also be graded by this system if available, and will be graded by blinded observers using the Oxford scale, a validated and reliable system for ocular surface complications [63, 64].

• 6.Meibomian gland atrophy

  Infrared imaging of upper and lower lids using Lipiscan (Johnson & Johnson). Graded by a blinded evaluator using Pult’s meiboscale, a validated and repeatable grading system [65, 66].

• 7.Adverse events

  Collected via a structured questionnaire assessing tolerability of both interventions (cyclosporine and IPL). Includes binary and open-ended questions to capture unexpected events.

• 8.Best-corrected distance visual acuity (BCDVA)

  Assessed at each visit prior to other procedures for safety monitoring.

• 9.Intraocular pressure (IOP)

  Measured at each visit for safety. Although no known IOP elevation has been associated with IPL or topical cyclosporine, monitoring is included due to the novelty of the treatments.

Participant timeline {13}

See Table 1.

Table 1.

Study activities for each visit

Legend: An X means that the task is performed, or the data is collected during the visit concerned by the column. An empty space means that the task or the data is not performed or collected during the visit concerned by the column

Sample size {14}

The standard deviation (SD) of the f-CLDEQ-8 was estimated at 4.6, based on participants with scores ≥ 12 in the f-CLDEQ-8 validation study, given the similarity to the target population [51]. Using a one-tailed independent samples t-test, a statistical power of 0.80, and SD of 4.6 yield a required sample size of 36 participants (18 per group) to detect a statistically significant difference at a 0.05 significance level; this would allow to detect an effect size of 0.870, relatively close to the Cohen’s theoretical definition of a large effect size of 0.8. Counting an anticipated loss to follow-up of 20%, a total of 22 participants per group (44 total) will be recruited.

Recruitment {15}

Participant recruitment will be conducted by optometrists affiliated with the clinical site involved in the study (18 optometrists across 6 locations). Eligible patients identified during routine eye examinations will be informed about the study and offered the opportunity to share their contact information with the research team. Additionally, informational posters featuring a study description and a QR code linking to the principal investigator’s email will be displayed in all participating clinics to facilitate self-referral.

Assignment of interventions: allocation

Sequence generation {16a}

Participant allocation will be stratified based on baseline f-CLDEQ-8 scores to control for symptom severity, a key factor influencing treatment response [67]. Participants will be categorized as having moderate (score 12–17), severe (score 18–24), or very severe symptoms (score ≥ 25). Within each stratum, randomization will occur in blocks of six using pre-generated allocation sequences. Participants will be assigned in the order they contact the research team. A random number generator will select the sequence for each block, ensuring balanced group assignment within each severity category.

Concealment mechanism {16b}

Blinding of study personnel does not apply in this context, as the principal investigator will be aware of group allocation due to the nature of the interventions. Participants will be blinded to their allocation, and study procedures are designed to be identical in both groups. The use of a sham IPL procedure replicating the visual and auditory experience of active treatment ensures participant blinding is maintained, minimizing potential bias in subjective outcomes. Outcome assessors for objective measures, such as imaging and staining analysis, will remain blinded to group assignment in order to ensure unbiased ratings.

Implementation {16c}

Allocation sequence and group allocation will be conducted by one of the principal investigators. Participant enrollment will be conducted by both the principal investigators, other volunteer optometrists on site, as well as clinic staff trained for the matter.

Assignment of interventions: blinding

Who will be blinded {17a}

Participants will be blinded to group allocation. Due to the use of opaque protective eye shields—required for IPL safety—participants will be unable to see whether the IPL device has been fitted with the active or sham light blocker, preserving blinding across both arms. Outcome assessors responsible for grading conjunctival staining and other image-based metrics will also remain blinded to group allocation. Blinding will be maintained by transmitting de-identified images and videos electronically. The investigator performing the interventions and data collection will not be blinded, as blinding at this level was not feasible due to safety requirements and resource constraints.

Procedure for unblinding if needed {17b}

Unblinding of a participant will occur only if a persistent visual disturbance is reported following an intervention session (IPL or sham–IPL) and a reduction in best-corrected visual acuity (BCVA) is confirmed relative to the participant’s baseline. In such cases, group allocation will be disclosed to the participant for clinical management, and their participation in the study will be discontinued.

Data collection and management

Plans for assessment and collection of outcomes {18a}

Primary data collection will occur at visit 1 (baseline), visit 2, and visit 5 for all outcomes, except meibography, which will be performed only at visits 1 and 5 (see participant timeline, Table 1). The primary outcome, the f-CLDEQ-8 questionnaire, will be administered at every visit. This questionnaire accounts for symptoms of both eyes, but results in a single score (between 1 and 37) for each completer. The f-CLDEQ-8 has demonstrated high test–retest reliability (ICC = 0.944), strong internal consistency (Cronbach’s α = 0.928), and good correlation with overall contact lens satisfaction [51]. A score ≥ 12 is indicative of contact lens discomfort, with a minimal clinically important difference (MCID) of 3 points and robust responsiveness and dose–response characteristics [53, 68]. The use of the CLDEQ-8 is endorsed by the Tear Film and Ocular Surface Society (TFOS) International Workshop on Contact Lens Discomfort as the only short, validated tool specific to contact lens–related dry eye [52]. TFOS also recommends collecting data on daily lens wearing time and using numeric global rating scales to further assess treatment efficacy in clinical trials.

Fluorescein tear break-up time (TBUT) is a standard method for assessing tear film stability, with a reported sensitivity of 72.2% and specificity of 61.6% using a diagnostic threshold of 10 s [62]. TBUT will be measured by instilling fluorescein using a moistened strip (with 2 drops of saline) on the superior bulbar conjunctiva, followed by slit-lamp examination using a cobalt filter and a handheld yellow filter to enhance fluorescein visualization. Three measurements per eye will be recorded, starting 30 s after instillation [69]. Non-invasive TBUT (NIBUT) will be assessed using the Tear Film Surface Quality (TFSQ) function of the Medmont E300 topographer. This method has demonstrated high repeatability and diagnostic accuracy, with a sensitivity of 82% and specificity of 94% at a cut-off of 12.1 s for dry eye diagnosis [61]. While the validity of NIBUT and TFSQ measurements over contact lenses has not been established in peer-reviewed studies, the method has been utilized in a randomized controlled trial published in 2018 [70].

Tear osmolarity will be assessed using the i-Pen handheld osmometer, which has demonstrated strong correlation with other clinical signs and symptoms of dry eye. At a diagnostic threshold of 318 mOsm/L, the i-Pen shows a sensitivity of 90.9% and specificity of 90.6% for detecting dry eye disease [55]. In vitro studies have confirmed its repeatability and validity in measuring osmolarity in fluid samples [56]. In this study, osmolarity will be measured at the inferior palpebral conjunctiva while contact lenses remain in place to avoid reflex tearing that may occur with lens removal [71]. Tear volume will be evaluated by measuring inferior tear meniscus height using the Myah’s automated analysis function, which captures measurements at five distinct points along the inferior meniscus. Although not a validation study, one recent publication using this function of the Myah in post-LASIK participants exists [58].

Corneal and conjunctival staining will be assessed using sodium fluorescein and lissamine green, instilled respectively onto the superior bulbar conjunctiva and the inferior fornix of each eye. Corneal images will be captured 30 s after fluorescein instillation [69] using a slit lamp with cobalt and handheld yellow filters, while conjunctival images will be taken without filters. A smartphone imaging system (Microrec adapter with iPhone 14) will be used to standardize image acquisition. Corneal staining will be graded using the AOS (Automated Ocular Surface) platform, which has demonstrated good reliability for anterior segment analysis [63]. Conjunctival staining will be evaluated using the Oxford grading scale, a validated tool for ocular surface complications that is widely used in research and accounts for nasal and temporal staining [72]. Meibomian gland atrophy will be evaluated with Lipiscan meibography of both upper and lower lids. Images will be assessed by a blinded grader using Pult’s meiboscale (0–4), which offers high inter- and intra-rater reliability and the best repeatability among subjective grading systems [65, 66]. Intraocular pressure (IOP) will be measured using a non-contact (air-puff) tonometer to avoid the need for topical anesthetic drops.

Plans to promote participant retention and complete follow-up {18b}

A follow-up telephone call will be conducted three weeks after visit 1 to assess adherence to the cyclosporine regimen, address any concerns, and encourage continued participation. Participants will be educated on potential benefits and cost of these treatments outside of the study. If a participant were to drop out after randomization, efforts would be made to remotely obtain primary outcome data (f-CLDEQ-8 scores) at timepoints identified in the protocol.

Data management {19}

A standardized paper case report form (CRF) will be used to document all non-image and non-video data, including best-corrected visual acuity (BCVA), intraocular pressure (IOP), and procedural notes related to image and video acquisition during study visits. Each entry will follow a consistent anonymized coding structure (e.g., ParticipantID_V1_NIBUT_OD), with no inclusion of participant names or group allocation identifiers. The CRF will also be used to record treatment administration details.

Digital data (e.g., topography, osmolarity, and imaging files) will be stored on password-protected clinic computers with secure cloud-based backup systems. Physical paper records will be securely stored in a locked cabinet at the Research Centre on Aging at the Université de Sherbrooke, within the office of the principal investigator. All data handling procedures will comply with institutional data protection and confidentiality standards.

Confidentiality {27}

Each participant will be assigned a unique alphanumeric identifier, which will be used on all study-related documents and data files, with the exception of the informed consent form. Consent forms will be stored securely in a locked drawer in the office of the principal investigator at the Research Centre on Aging, Université de Sherbrooke. A single password-protected electronic file linking participant identifiers to their full names will be maintained on a secure computer. Access to this file will be restricted to the principal investigator and a designated research assistant. This linkage document is necessary solely for administrative follow-up and will not be used in data analysis, ensuring participant confidentiality is preserved throughout the study.

Plans for collection, laboratory evaluation and storage of biological specimens for genetic or molecular analysis in this trial/future use {33}

Non-applicable: no biological specimens will be collected.

Statistical methods

Statistical methods for primary and secondary outcomes {20a}

Descriptive statistics will be computed for each group at baseline. The primary outcome will be the change in mean f-CLDEQ-8 score from baseline to week 16 within each group. A one-tailed independent samples t-test will be used to assess the statistical significance of the between-group difference in symptom change. To evaluate the effect of cyclosporine alone, a paired t-test will also be conducted comparing baseline and week 8 f-CLDEQ-8 scores across all participants prior to the IPL or sham intervention. Additional symptom-related data collected longitudinally will be analyzed using repeated measures regression models, which are appropriate for handling intra-subject correlations over time and assessing time-by-treatment interactions, allowing for robust inference while accounting for repeated measures within participants. For secondary outcomes, the effect of treatment will be evaluated using statistical analyses selected based on the type of variable and accounting for the nested data structure (eyes within subjects). Continuous variables measured in both eyes—such as baseline to week 16 difference in fluorescein TBUT, NIBUT, tear osmolarity, and tear meniscus height—will be analyzed using multilevel (hierarchical) linear models. Improvement or not in the grading for meibomian gland atrophy scores and corneal and conjunctival staining scores will be analyzed using generalized linear models (GLMs) with a logistic link function, given the binary nature of these variables.

Interim analyses {21b}

Interim safety analyses will be conducted after approximately half of the participants have completed the study, and after all participants have completed the study. These analyses will focus on safety-related variables, including best-corrected visual acuity (BCVA), intraocular pressure (IOP), and the incidence of adverse events. Statistically significant reductions in BCVA, increases in IOP, or the occurrence of serious adverse events in either group will be flagged as potential stopping criteria for further ethical and safety review.

Methods for additional analyses (e.g. subgroup analyses) {20b}

At this time, the only planned additional analysis is to evaluate whether soft contact lens (SCL) wearing modality (daily disposable vs. monthly/bi-monthly replacement) influences treatment outcomes. This variable will be included as a fixed effect in the mixed-effects model. No other additional analyses are currently planned; however, exploratory post-hoc analyses may be conducted if notable trends emerge within specific participant subgroups.

Methods in analysis to handle protocol non-adherence and any statistical methods to handle missing data {20c}

In the event of participant dropout, consent will be sought to maintain limited contact for follow-up purposes. The f-CLDEQ-8 questionnaire will continue to be sent to these participants according to the original data collection schedule to minimize missing data. Analyses will follow the intention-to-treat (ITT) principle, and sensitivity analysis with dropouts using different approaches could be used to deal with their missing values.

Plans to give access to the full protocol, participant level-data and statistical code {31c}

Upon study completion and publication of the primary results, access to the full study protocol, anonymized participant-level data, and statistical code will be made available upon reasonable request to the principal investigator. Requests must include a clear research purpose and will be subject to approval by the research ethics board and data-sharing agreement requirements to ensure participant confidentiality and compliance with applicable regulations. Data and code will be shared in de-identified formats compatible with standard statistical software.

Oversight and monitoring

Composition of the coordinating centre and trial steering committee {5d}

The coordination center for the study will consist of the principal investigators—two full professors with expertise in clinical research—and a doctoral student in charge of study operations. Additionally, the optometrist and clinic owner where the study is conducted will contribute to site-level coordination. The PhD student will be responsible for participant management and data collection. The principal investigators will supervise informed consent procedures, provide oversight of day-to-day study conduct, address operational issues, ensure proper data storage and confidentiality, and monitor budgetary and resource management. A trial steering committee (TSC) will be established to provide independent oversight of the study. The TSC will include one independent optometrist–clinician with formal research training, a professor from the Université de Montréal School of Optometry, a faculty member from an academic department unrelated to the study investigators, and the three principal investigators. The committee will convene at half of participant completion and prior to final data analysis. The TSC will review study progress, safety findings, protocol adherence, and interim results. A final meeting will be held to determine the strategy for data interpretation and dissemination of results in accordance with ethical and scientific standards.

Adverse event reporting and harms {22}

Adverse events (AEs) will be systematically recorded using a custom-designed questionnaire developed for this study. The questionnaire is structured in two sections corresponding to the two interventions under investigation: topical cyclosporine 0.09% and intense pulsed light (IPL) therapy. The first section assesses adverse effects related to cyclosporine use. Participants will rate the intensity of discomfort and blurred vision experienced during instillation on a Likert scale. An open-ended question follows, allowing participants to report any additional symptoms they attribute to cyclosporine use. The second section focuses on IPL-related adverse effects. Participants will indicate the presence or absence of predefined symptoms, and, if present, grade their severity on a 0–10 numeric rating scale. Symptoms assessed include periocular pain, ocular pain, burning sensation, eyelash loss, ocular redness, skin redness, and blurred vision. For each symptom, participants will provide ratings across three timeframes: during the procedure, within 12 h post-treatment, and during the subsequent three weeks. An additional open-ended item allows participants to report and grade any other adverse events they believe to be associated with IPL.

Frequency and plans for auditing trial conduct {23}

An oversight committee comprising the principal investigators and some other researchers in the field that are not directly implicated in the study will convene after half of the participants have completed the study. The committee will audit trial conduct and review collected data, with particular focus on safety outcomes including visual acuity, intraocular pressure, and adverse events.

Plans for communicating important protocol amendments to relevant parties (e.g. trial participants, ethical committees) {25}

The ethics committee will be automatically notified via the web platform upon submission of any protocol amendment. Study activities will be suspended until formal approval is granted. Research team members not directly involved in data collection will be informed of the amendment via email. All participants, including those who have completed their study visits, will be contacted by telephone. Updated informed consent will be obtained from each participant, with specific emphasis on the nature and implications of the protocol changes.

Dissemination plans {31a}

Study findings will be disseminated through poster presentations and multiple peer-reviewed publications (anticipated between one and four). Each publication will focus on a distinct aspect of the dataset according to the specified objectives.

Discussion

Several elements of this study address novel research questions. To the best of the authors’ knowledge, no prior data exist on the effects of 0.09% cyclosporine nanomicellar eye drops in contact lens–induced dry eye (CLID), nor on the combined use of cyclosporine and intense pulsed light (IPL) therapy. Given the exploratory nature of objective 3 and the absence of an established comparator, a pre-post design without placebo control was deemed appropriate, despite the inherent risk of bias. Participant recruitment was intentionally broad to reflect the diverse population of symptomatic contact lens wearers encountered in clinical practice. As both dry eye disease and CLID are predominantly symptom-driven conditions, eligibility was based primarily on symptomatology rather than objective clinical signs. A key limitation of the study is the inability to implement double-blinding. The principal investigator will conduct both the interventions and data collection, making blinding of the treatment provider infeasible due to the visible nature of the IPL procedure. However, outcome assessment will be performed by blinded raters or automated analysis systems to mitigate bias.

Potential confounding factors must also be considered in the interpretation of results. A treatment sequence (order) effect is possible, wherein the preceding administration of cyclosporine may influence the subsequent effect of IPL by overlapping mechanisms of action. Additionally, a dose–response effect may be present, as cyclosporine administered twice daily over 16 weeks may continue to exert increasing therapeutic benefit over time. Prior studies suggest peak effects for some signs at around 56 days, with continued improvement thereafter [30, 73]. Consequently, it may be difficult to fully distinguish the additive effect of IPL from the cumulative effects of prolonged cyclosporine use in the final outcome analysis.

Compliance represents a potential limitation in this study, particularly for the pharmacological intervention, which relies on self-administration of cyclosporine eye drops. Unlike the IPL treatment, which is administered in-clinic by the research team, adherence to the topical regimen cannot be directly observed. To monitor compliance, participants will receive biweekly electronic prompts asking how many doses were missed in recent days. Although this self-reporting method has limitations, it offers a practical alternative to more intrusive strategies such as collecting used vials, which are also prone to bias [74].

Selection of outcome measures presented an additional challenge, given the absence of consensus on the optimal clinical variables to characterize contact lens–related dry eye and discomfort [52]. Outcome selection prioritized objective, previously studied variables that are relevant to the expected mechanisms of action of the interventions, while also considering the need to minimize participants’ burden and ensure procedural feasibility within the study context.

This study has several methodological strengths. Randomization is employed to minimize selection bias and ensure balanced baseline characteristics between groups. The inclusion of a control group receiving sham IPL allows for the isolation of IPL-specific effects in participants already treated with cyclosporine, controlling for placebo effects and the natural progression of improvement associated with ongoing pharmacologic therapy.

Blinded assessment further strengthens internal validity. Conjunctival staining and meibography will be graded by independent, masked clinicians, while corneal staining will be evaluated using an automated artificial intelligence platform, enhancing objectivity and reproducibility.

The primary outcome is measured using the f-CLDEQ-8, a validated French translation of the CLDEQ-8, which is widely recognized as the gold standard for assessing contact lens discomfort in clinical research. Moreover, statistical analyses will employ models that account for inter-eye correlation, enabling full use of bilateral data while mitigating the risk of inflated type I error—an approach recommended for ophthalmic studies involving paired data [75].

This study has several limitations that should be acknowledged. Contact lens–induced dryness (CLID) is influenced by a wide range of confounding factors—including lens material, fit and curvature, replacement schedule, care solutions, wear history, ocular surface characteristics, environmental exposures, occupation, and cosmetic use—many of which cannot be fully controlled within the scope of this study. These factors may affect both the severity of symptoms and the response to treatment. Another limitation is the absence of a direct biomarker for ocular surface inflammation. Although matrix metalloproteinase-9 (MMP-9) is a validated marker commonly used in dry eye research, the necessary diagnostic device was not available within the study’s budget. As an alternative, tear osmolarity will be assessed, which has been shown to correlate with MMP-9 levels and serve as an indirect indicator of inflammation [76]. Blinding of the investigator performing the interventions is not feasible due to the in-clinic nature of IPL administration and the skill required, which introduces the potential for performance bias. Additionally, the primary outcome—symptom severity as measured by the f-CLDEQ-8—is inherently subjective. Participant-reported outcomes may be influenced by social desirability bias or expectations related to treatment, which could affect the observed symptom changes.

Trial status

A pilot study was conducted in fall 2023 to assess feasibility. Recruitment for the main randomized controlled trial commenced in April 2024. The study is currently being conducted under protocol version 3, finalized in February 2024. Recruitment is expected to be completed by the end of March 2026.

Abbreviations

MGD

Meibomian gland dysfunction

CLID

Contact lens induced dryness

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 Questionnaire-8

TMH

Tear meniscus height

SCL

Soft 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

Authors’ contributions {31b}

ELM, as the first author, drafted the study protocol and prepared the initial manuscript. LM contributed to the design of the clinical components and outcome measures and was equally involved in the critical revision and editing of the manuscript. MFD contributed to the methods and statistical analysis plan. PB contributed to the overall development of the protocol, provided primary supervision of the first author, and shared equal responsibility for manuscript revision and editing.

Funding {4}

This study is supported by four funding sources. First, the Canadian Optometric Education Trust Fund (COETF) awarded a grant in 2021. Second, additional support was provided by the American Academy of Optometry Foundation through the 2024 Centennial Ezell Fellowship and the 2025 Bert C. and Lydia M. Corwin Ezell Fellowship, with the associated financial award allocated to this research. Third, funding was obtained via a MITACS grant, co-funded by Sun Pharma, which also supplies the Cequa (cyclosporine 0.09%) eye drops used in the study at no cost. Fourth, the Canadian Consortium of Clinical Trials Training (CANTRAIN) provided a doctoral studentship award in 2024–2025, sponsored by the Canadian Institute of Health Research and the Quebec Research Fund – Health (FRQS). All data collection, analysis, and dissemination are conducted independently by the Université de Sherbrooke and the research team. The COETF, the American Academy of Optometry Foundation, CANTRAIN, and Sun Pharma have no ownership of the data and no influence over data analysis or publication of the results.

Data availability {29}

De-identified individual participant data and raw datasets will be made available upon reasonable request to the research team. Access will be granted to qualified academic researchers who provide a clear rationale for their request, including intended use and a data management plan ensuring secure storage and confidentiality. Initially, access to the full dataset will be restricted to the research team (the authors of this protocol). There are no contractual agreements restricting or mandating data sharing.

Declarations

Ethics approval and consent to participate {24}

This study has been approved by the Comité d’éthique à la recherche du CIUSSS de l’Estrie–CHUS (Project No. 2024–5200). The ethics committee reviewed and approved all study-related materials, including the informed consent forms, questionnaires, recruitment documents, funding sources, and the project’s scientific justification. Participants will receive an information and consent form written in plain language, available in both English and French. This document will be sent via email prior to visit 1, allowing participants sufficient time to review the study details. The research team will be available by email or phone to address any questions. Informed consent will be reconfirmed prior to each intervention, and participants will retain the right to withdraw from the study at any time without providing a reason.

Consent for publication {32}

Not applicable.

Competing interests {28}

ELM received honoraria for a one-time consulting contract with Sun Pharma in 2021, prior to the design of this study. He also received honoraria from CooperVision in 2024, and from Johnson and Johnson in 2025 as well as funding support from the Canadian Optometric Education Trust Fund, the American Academy of Optometry Foundation, and CANTRAIN in previous years. LM has received honoraria and/or research funding from Bausch and Lomb, Johnson and Johnson, Cooper Vision, Sun Pharma, Thea, and EssilorLuxottica in the past years. MFD has no competing interest. PB has no competing interest.