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. 2026 Sep 6;20:610688. doi: 10.2147/OPTH.S610688

The Effect of Varenicline Nasal Spray on the Signs and Symptoms of Dry Eye Disease and Tear Film Stability: A Randomized Controlled Trial

P Dee Stephenson 1,✉, Cynthia Matossian 2
PMCID: PMC13560946  PMID: 42724843

Abstract

Purpose

To evaluate the effect of varenicline nasal spray (VNS) 0.03 mg on the signs and symptoms of dry eye disease (DED) and tear film stability.

Patients and Methods

In this prospective, placebo-controlled study, 50 DED subjects were randomized to receive either VNS 0.03 mg nasal spray or its vehicle twice daily for 28 days. Study parameters included dry eye questionnaire score (DEQS), eye dryness score (EDS), corneal (CFS) and conjunctival fluorescein staining, non-invasive tear break-up time (TBUT), surface asymmetry index (SAI), and surface regularity index (SRI).

Results

Post treatment, the improvement in mean symptom scores, including DEQS (23% vs 12%, p=0.022) and EDS (44% vs 27%, p = 0.012), was significantly higher in the VNS group compared to the vehicle group. The mean CFS and conjunctival staining scores also showed significantly higher improvement (~50% vs ~20%, p<0.001) in the VNS group compared to the vehicle. The mean change in non-invasive TBUT was higher in the VNS group (70% vs 30%, p = 0.680). The mean improvement in SAI and SRI were comparable between the two groups. There were no serious adverse events in either group.

Conclusion

There was a statistically significant improvement in the symptoms and signs of DED in the VNS group. These results indicate that improving natural tear production using VNS nasal spray can help foster tear film stability and ocular homeostasis over time.

ClinicalTrials.Gov Identifier

NCT05514041.

Keywords: dry eye disease, varenicline nasal spray, tear film stability, VNS

Introduction

Dry eye disease (DED) is a multifactorial ocular surface disease characterized by a loss of tear film homeostasis resulting in tear film instability, hyperosmolarity, and inflammation of the ocular surface. It is a growing public health concern with a significant negative effect on patients’ quality of life.1 Increased tear evaporation and/or reduced tear production are the major causes of DED.2,3

The primary goal for DED management is to restore tear film and ocular surface homeostasis.4,5 Tear film comprises two main layers: the muco-aqueous and lipid layers, both of which are integral to preserving tear film homeostasis.6,7 Conventionally, artificial tears have been used to replace or supplement the aqueous component of the tear film and address aqueous-deficient DED.8 Lipid-containing eye drops were developed to more closely mimic the combination of aqueous and lipid layers of the tear film.9 Over the last 15 years, restoration of the natural lipid layer using thermal pulsation treatments has been found to be effective.10–13 These in-office procedures are effective at removing meibomian gland obstruction, improving tear film stability, and addressing the evaporative DED. More recently, understanding of the neural control of the tear film and the dynamic interplay between the nasolacrimal reflex (NLR) and lacrimal functional unit (LFU) has led to novel treatment methods that can increase natural tear production and address aqueous-deficient DED.

Tear production is primarily regulated by the LFU, which comprises the lacrimal glands, ocular surface (cornea, conjunctiva, goblet cells, and meibomian glands), eyelids, and associated sensory and motor innervations of the nervous system. The trigeminal afferent nerves in the cornea and conjunctiva regulate approximately two-thirds of the tear secretions, and those in the nasal cavity account for approximately one-third of basal tear film production.14,15 Stimulating tear production via the trigeminal parasympathetic pathway (TPP) offers a novel, non-invasive, targeted approach to improving tear film homeostasis and managing DED.

Varenicline solution nasal spray 0.03 mg (TYRVAYA®; Viatris Inc., Canonsburg, PA) (VNS), is a pharmacologic option to stimulate natural tear production,14,16 and address the signs and symptoms of DED. Approved by the FDA in 2021, VNS is a highly selective nicotinic acetylcholine receptor (nAChR) agonist,14 that targets receptors on the trigeminal nerve terminating in the nasal cavity, thereby activating tear production through the parasympathetic pathway. The efficacy and safety of VNS were demonstrated in ONSET-1 (Phase 2) and ONSET-2 (Phase 3) trials.3,17–19 Assessment of tear film stability is crucial when evaluating the ability of a nasal spray to restore ocular surface homeostasis. As such, the present study was designed to extensively evaluate the efficacy and safety of VNS in addressing the clinical signs and symptoms of DED, improving patient quality of life and tear film stability.

Materials and Methods

Study Design and Study Population

This was a prospective, randomized, placebo-controlled, double-masked, investigator-initiated study (NCT05514041, clinicaltrials.gov) of subjects with DED, conducted at Stephenson Eye Associates, Venice, FL, USA, from October 2022 to December 2023. The study adhered to the tenets of the Declaration of Helsinki, which are consistent with the International Council for Harmonization (ICH) guidelines for Good Clinical Practice and applicable regulatory requirements. The protocol and informed consent form were approved by an independent ethics committee, WCG IRB (Cary, NC, USA; IRB tracking number 20223675), and all subjects provided written informed consent.

The study aimed to enroll 50 adult DED subjects aged ≥22 years. The diagnosis of DED was based on an Ocular Surface Disease Index (OSDI) score ≥13, and a corneal fluorescein staining (CFS) score of ≥2 in at least one corneal region (or a total score of ≥4 across all regions) using the National Eye Institute/Industry Workshop Scale. Additional eligibility criteria included an abnormal Cassini surface qualifier image determined by an experienced masked investigator, a willingness to provide informed consent, the ability to self-administer the study drug as per protocol, and complete questionnaires independently.

Subjects were excluded if they had active ocular herpes simplex/zoster infections, significant eyelid inflammation or abnormalities, ocular trauma, or recent ocular surgeries (within six months). Nasal conditions, such as untreated infections, vascularized nasal polyps, significant nasal obstruction, or a history of nasal or sinus surgery, were also exclusionary. Additionally, subjects were excluded if they had used certain ophthalmic treatments (eg, cyclosporine, lifitegrast, or corticosteroids) within 6 months prior to the screening/baseline visit and during the treatment period or undergone procedures (eg, thermal pulsation, intense pulsed light therapy) within 6 months prior to the screening/baseline visit. Subjects with hypersensitivity to study drug components or those participating in other investigational studies within 30 days prior to baseline were also excluded. Artificial tears were permitted but restricted within two hours of study visits. Pregnant, nursing, or potentially pregnant individuals were also excluded.

Randomization and Intervention

Eligible subjects were randomized in a 1:1 ratio to study and control groups. Simple randomization using random number tables was used to generate the random allocation sequence by the study coordinator. Sequentially numbered, sealed, opaque envelopes were used to conceal the sequence. Subjects in the study group received VNS, and the control group received vehicle (placebo-phosphate-buffered saline) nasal spray, each used twice daily (BID) for 28 days. The eye that met all inclusion criteria was the study eye. If both eyes were qualified, the study eye was the one with the most rapid tear break-up time (TBUT). If there was no difference in TBUT, the eye with a greater degree of total corneal staining at baseline was the study eye. If no difference was found for either measure, the right eye was designated as the study eye.

The study drugs (VNS and placebo) were indistinguishable based on appearance, consistency, and packaging (bottle size, shape, color, labeling, etc). All subjects, investigators, and site personnel performing study assessments were masked to the study medication throughout the study.

Study Assessments

Patients in both groups were assessed for the mean change in the subjective symptoms and clinical signs of DED. Assessments of subjective symptoms included mean change in the Eye Dryness Score (EDS) from baseline to Day 28 and mean change in the Dry Eye-Related Quality of Life Score (DEQS) from baseline to Day 21. DEQS was assessed at Day 21 (seven days prior to the assessment of EDS at Day 28) to reduce response burden on the patients and prevent patient fatigue. The assessment of clinical signs included mean change from baseline to Day 28 in the non-invasive TBUT (using Tearcheck by E-Swin, Bridgeton, MO), CFS (using 2% preservative-free sodium fluorescein solution), and conjunctival staining (using 2% preservative-free sodium fluorescein solution). In addition, the mean change (from baseline) in the topographic indices (Surface asymmetry index (SAI) and Surface regularity index (SRI); Cassini, i-Optics, The Hague, Netherlands) was assessed on Day 1 (15 minutes after treatment) and on Day 28. Safety parameters included monitoring of adverse events (AEs) and serious adverse events (SAEs).

DEQS assessed the impact of DED on quality of life. The validated questionnaire included 15 questions − 6 about bothersome ocular symptoms and 9 on the impact of DED on daily life. A quality-of-life score ranging from 0 (no disability) to 100 (maximum disability) was calculated.20 EDS, also a validated questionnaire, utilized a 0–100 Visual Analog Scale (VAS), where 0 represented no discomfort and 100 represented maximal discomfort.21 Corneal and conjunctival fluorescein staining was graded using the National Eye Institute/Industry Workshop Scale (0–3 per corneal region; maximum score of 15).22,23 Tear break-up time (TBUT) was recorded as the number of seconds that elapse between the last blink and the appearance of the first dry spot in the tear film. Modern corneal topographers can detect asymmetry or irregularities in the corneal surface caused by tear film disruption.24 Surface Asymmetry Index (SAI) values ranging between 0.10 to 0.42 are considered normal,25 while dry eye subjects fall between a range of 0.49 to 1.88.26–32 Similarly, SRI values ranging between 0.00 to 0.56 are considered normal.25,33 While a value between 0.41 to 2.33 has been reported in dry eye subjects.26–32,34 Ocular surface disease index (OSDI) is a validated 12-item scale measuring DED symptoms and their impact on vision, with higher scores indicating greater disability. Scores were categorized as normal (0–12), mild (13–22), moderate (23–32), and severe (>33).35

No formal sample size calculations were performed for this study. A sample size of 50 patients was chosen empirically.

Statistical Analysis

Data analysis was performed using SPSS (IBM SPSS Statistics 27, IBM Inc., Armonk, NY). Descriptive statistics were calculated for baseline demographic and clinical characteristics, including age, gender, race, ethnicity, and all baseline examination results, tabulated by treatment group. Continuous variables were presented using the mean and standard deviation (SD). The normality of continuous data was assessed using the Shapiro–Wilk test.

For normally distributed continuous variables, the two groups were compared using an Independent t-test. For data that were not normally distributed or for ordinal variables, the non-parametric Mann–Whitney U-test was employed. Categorical variables were summarized using counts and percentages and compared between groups using Chi-square tests.

Results

Demographics and Baseline Characteristics

Table 1 summarizes the demographic and baseline characteristics of the study (VNS) and vehicle groups. Twenty-five subjects were enrolled in the VNS group and twenty-five in the vehicle group. All randomized subjects received the intended treatment and were analyzed. No subjects were lost to follow-up, and the analysis was carried out on a total of 25 patients from both groups.

Table 1.

Demographics and Baseline Characteristics

Study Group Vehicle Group p-value
N 25 25
Age, years (Mean ± SD) 70.2 ± 9.3 65.2 ± 14.7 0.409
Gender (%)
 Females 88% 80% 0.702
 Males 12% 20%
Race (%)
 White 96% 96% 1.000
 Other 4% 4%
Ethnicity (%)
 Not Hispanic or Latino 96% 100% 1.000
 Hispanic 4% 0%
Ocular Surface Disease Index (OSDI) (Mean ± SD) 58.66 ± 24.62 53.18 ± 23.30 0.423
Dry Eye-Related Quality of Life Score (DEQS) (Mean ± SD) 42.07 ± 13.61 35.13 ± 15.69 0.102
Eye Dryness Score (EDS) (Mean ± SD) 47.80 ± 22.92 41.48 ± 24.25 0.348
Corneal Fluorescein Staining (Mean ± SD) 10.32 ± 3.40 8.36 ± 3.16 0.053
Conjunctival Staining (Mean ± SD) 13.12 ± 3.78 10.48 ± 3.64 0.015
Tear breakup time (TBUT) (Mean ± SD) 2.96 ± 2.65 4.02 ± 3.34 0.119
Surface Asymmetry Index (SAI) (Mean ± SD) 0.68 ± 0.47 1.03 ± 0.80 0.143
Surface Regularity Index (SRI) (Mean ± SD) 0.18 ± 0.13 0.30 ± 0.26 0.073
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At baseline, the two groups were comparable in terms of demographics (age, gender, race, and ethnicity) and baseline characteristics such as OSDI, DEQS, EDS scores, CFS scores, TBUT, and topographic indices (SAI and SRI).

Study Endpoints

The VNS study group showed a statistically significantly higher improvement in the subjective symptoms of DEQS from baseline to Day 21 compared to the vehicle group (mean change: −9.6 ± 13.03 vs −4.13 ± 8.70, respectively; p = 0.022, Figure 1). The improvement in the EDS score was also found to be statistically significantly higher in the VNS group (mean change: −21.04 ± 20.98 vs −11.28 ± 22.34, respectively; p = 0.012, Figure 2).

Figure 1.

A bar graph showing the change in DEQS score from baseline to Day 21 for the study group and the vehicle group.

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The mean change (from baseline to Day 21) in dry eye-related quality of life score (DEQS) in the study and vehicle groups.

Figure 2.

A bar graph showing change in EDS score from baseline to Day 28, with larger negative shift for study arm than vehicle, with p equals 0.012.

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The mean change (from baseline to Day 28) in eye dryness score (EDS) in the study and vehicle groups.

The objective signs of DED (corneal fluorescein and conjunctival staining) by a masked observer demonstrated a statistically significantly higher mean improvement in the VNS group compared to vehicle (CFS: −5.75 ± 3.77 vs −1.52 ± 4.15, p <0.001, and conjunctival staining: −8.00 ± 4.40 vs −2.20 ± 5.17, p <0.001, respectively, Figures 3 and 4).

Figure 3.

A bar graph showing change in corneal fluorescein staining score from baseline to Day 28 by group.

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The mean change (from baseline to Day 28) in corneal fluorescein staining (CFS) score in the study and vehicle groups.

Figure 4.

A bar graph showing change in conjunctival staining score from baseline to Day 28, with a larger negative score shift in the study arm than in the vehicle arm.

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The mean change (from baseline to Day 28) in conjunctival staining score in the study and vehicle groups.

The mean change in TBUT (from baseline to Day 28) was not significantly different between groups; however, the improvement was higher in the VNS group compared to the vehicle group (2.02 ± 3.54 vs 1.18 ± 2.42, p = 0.680) (Figure 5). The mean change (from baseline to 15 minutes post administration on Day 1) in the corneal topography indices of SAI (0.02 ± 0.41 vs 0.16 ± 0.45, p = 0.260) and SRI (−0.02 ± 0.11 vs −0.04 ± 0.19, p = 0.928) revealed no significant differences between the study and the vehicle control groups. A similar trend was observed at Day 28, with both groups demonstrating no significant differences in the mean change in SAI (−0.13 ± 0.31 vs 0.29 ± 1.22, p = 0.073) and SRI (−0.04 ± 0.11 vs −0.01 ± 0.23, p = 0.727) from baseline to Day 28.

Figure 5.

A bar graph showing changes in TBUT score from baseline to Day 28, with small increases in both groups and a non-significant difference (p equals 0.680).

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The mean change (from baseline to Day 28) in tear break-up time (TBUT) in the study and vehicle groups.

Sneezing was the most frequently observed adverse event in the VNS group (in 88% of subjects vs 4% in the vehicle group). Other AEs reported in the VNS group were burning sensation (n = 3) and runny nose (n = 1). One patient in each group experienced a nosebleed. All AEs were mild and resolved without additional intervention.

Discussion

This randomized, double-masked, placebo-controlled study evaluated the efficacy and safety of 0.03 mg VNS for treating DED. The effect of VNS on subjective symptoms and clinical signs of DED was compared to the vehicle control nasal spray. VNS-treated patients demonstrated a statistically significantly higher improvement in the mean DEQ scores compared to the patients in vehicle control (23% vs 12%, p = 0.022). The DEQS questionnaire is a validated questionnaire for evaluating the multifaceted effects of DED on patients’ daily lives.36–38 The higher reduction in the mean DEQS scores from baseline to posttreatment Day 21, as observed in the present study, indicates that VNS treatment helped reduce the frequency and severity of dry eye symptoms and their impact on patients’ daily living, allowing VNS-treated patients to achieve better clarity of vision and higher tolerance to different lighting conditions. Following treatment, VNS patients were able to better concentrate and perform daily tasks such as reading newspapers or watching TV, and overall felt better while performing activities of daily living.

Eye Dryness Score (EDS), which measures the severity of DED on a VAS was also used to assess symptom improvement following study drug treatment. Patients receiving VNS demonstrated significantly higher improvements (from baseline to Day 28) in the mean EDS score (44% vs 27%, p = 0.012) compared to patients receiving vehicle nasal spray. These results align with the findings reported previously in the vehicle-controlled VNS studies, demonstrating a significantly higher improvement in the mean EDS scores in patients treated with 0.03 mg of VNS compared to vehicle control patients.17,18,39,40

The effect of VNS on DED was also supported by significantly higher improvements in both the corneal and conjunctival staining scores in patients receiving VNS compared to those receiving vehicle nasal spray. Following 28 days of treatment, patients in the study group demonstrated more than 50% reduction in the baseline corneal as well as conjunctival staining scores, compared to ~20% reduction observed in the vehicle control. The present study findings align with the previously published vehicle-controlled studies that demonstrated a statistically significantly higher improvement,17 or a trend of higher improvement in the CFS scores in the VNS group compared to the vehicle.3,18

A healthy and stable tear film contributes to ocular surface integrity and an optically smooth surface. The most commonly used technique for assessing tear film stability is the TBUT. In the present study, VNS-treated patients showed a trend towards higher improvement in mean TBUT (from baseline) compared to vehicle control patients. TBUT improved by nearly 70% in the VNS group compared to only ~30% in the vehicle control group; however, the difference between the two groups could not reach statistical significance.

Besides TBUT, tear film stability was also assessed using corneal topographical indices of SAI and SRI.30 These indices provide a detailed view of the corneal surface disruptions that are central to visual disturbances in DED, capturing the effects of tear film instability and epithelial damage. In the present study, there were no significant differences in the mean change in SAI and SRI between the two groups. While several previously published DED-related studies also assessed these topographic indices (SAI and SRI) in dry eye patients, there has been no clear consensus on the correlation of these parameters with DED.24,26,28,30,31,41,42 While 4 studies that compared SAI and SRI in dry eye and normal subjects reported significant differences in the SAI and SRI values among dry eye and normal subjects,26,30,31,42 others did not find any significant differences in these parameters among the dry eye and normal subjects.24,28,41 Similarly, the reduction in SAI/SRI values following different DED treatments has been reported;27,31,32,43–45 however, the reduction was significant in some studies,27,31,32,43 and not in others.44,45 The present study finding of no significant differences in the mean change in SAI and SRI following VNS/vehicle treatment adds to the growing body of evidence that these parameters have limited sensitivity in detecting subtle improvements in corneal surface dynamics and tear film stability.

VNS was well tolerated by patients. All enrolled patients completed treatment without discontinuation. Safety assessments revealed that all AEs were mild and resolved without intervention. Sneezing was the most common adverse event in the VNS group, occurring in 88% of subjects, consistent with the pharmacological effects of the treatment.

The significant improvements in subjective symptoms and clinical signs support the efficacy of VNS nasal spray as a viable treatment option for DED. Intranasal neurostimulation of TPP, a novel, non-invasive approach to promote tear film production and address DED, has many advantages. Since VNS activates the TPP of the nasal cavity, chronic DED patients with damaged trigeminal afferent corneal and conjunctival nerves can benefit from this treatment. DED treatment with intranasal spray may help reduce the burden of ocular drops in patients who are already on topical eye drops for other ocular conditions (eg, glaucoma), and address compliance issues in older patients who might have difficulty in drop administration (due to tremors, dexterity issues, or neck deformities).14 In contrast to topical eye drops, there is no risk of preservative-induced ocular toxicity as intranasal delivery spares the ocular surface.

Tear film stability is typically associated with a healthy lipid layer; however, VNS that improves the aqueous component of the tear film was found to improve TBUT in the present study. This highlights the complementary role of the aqueous and lipid layers in promoting tear film stability. Since DED patients are likely to have coexisting aqueous-deficient dry eye and meibomian gland dysfunction (MGD), the authors hypothesize that in patients where both conditions prevail, VNS treatment to improve the aqueous layer may be combined with MGD treatments to improve the lipid layer, providing a more stable tear film.

The study is limited by its small sample size and short follow-up. Future studies evaluating the long-term efficacy and patient compliance with nasal spray may provide more valuable insights into the novel treatment strategy of pharmacologic neuroactivation of tear film production to address the signs and symptoms of dry eye disease. Since dry eye is a multifactorial disease, a single treatment may not be sufficient to address the disease. As such, further studies to determine optimal strategies of combining VNS with existing treatments for restoring tear film homeostasis and improving dry eye symptoms are warranted.

Conclusion

In conclusion, this study highlights VNS as a safe and effective therapeutic option for improving both the clinical signs and symptoms of DED. These findings contribute to the growing body of evidence supporting non-invasive, neuromodulator approaches in ocular surface disease management.

Acknowledgments

The authors express their gratitude to Marguerite McDonald, MD, and Stephen D. Klyce, PhD, for their critical review of the manuscript and for offering valuable insights that contributed to its improvement. Additionally, appreciation is extended to Sarae Brubaker, certified Ophthalmic assistant (COA), for her assistance in data collection and special patient testing. Raman Bedi, MD, IrisARC - Analytics, Research & Consulting (Chandigarh, India), provided statistical and editorial assistance in preparing the manuscript.

Funding Statement

Funding for this study was supported by Viatris, Inc., Canonsburg, PA.

Abbreviations

DED, Dry eye disease; NLR, Nasolacrimal reflex; LFU, Lacrimal functional unit; VNS, Varenicline nasal spray; nAChR, Nicotinic acetylcholine receptor; ICH, International Council for Harmonization; OSDI, Ocular Surface Disease Index; CFS, corneal fluorescein staining; BID, Twice daily; TBUT, tear break-up time; EDS, Eye Dryness Score; DEQS, Dry Eye-Related Quality of Life Score; SAI, Surface asymmetry index; SRI, Surface regularity index; AEs, Adverse events; SAEs, Serious adverse events; VAS, Visual Analog Scale; SD, Standard deviation; TPP, Trigeminal parasympathetic pathway; MGD, Meibomian gland dysfunction.

Data Sharing Statement

The datasets generated during and/or analyzed during the current study are available from the corresponding author (PDS) on reasonable request.

Disclosure

Dr P Dee Stephenson reports support for the manuscript from VIATRIS, during the conduct of the study; grants or contracts from Dompe; Honoraria from Bausch & Lomb, Ocular Therapeutix, Lensar, Dompe, Sight Sciences, Viatris; data safety/advisory board participation from Bausch, Atia; leadership or fiduciary roles from Cedars Aspens, outside the submitted work. None of the authors has any other potential conflicts of interest to disclose.

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Data Availability Statement

The datasets generated during and/or analyzed during the current study are available from the corresponding author (PDS) on reasonable request.

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