Varenicline Nasal Spray for the Treatment of Dry Eye Disease Following Corneal Collagen Crosslinking

Corneal collagen cross-linking (CXL) is a procedure widely used by clinicians to stiffen the cornea and arrest the progression of corneal ectatic conditions such as keratoconus and post-laser in situ keratomileusis (LASIK) ectasia [1]. The introduction of CXL has dramatically altered the treatment paradigm of corneal ectatic disorders, and long-term data support the efficacy and long-term stability of the procedure [2]. Since its introduction, a number of different approaches have been described for performing CXL with the standard protocol approved by the Food and Drug Administration (FDA) including removal of the central corneal epithelium, known as the Dresden protocol [3]. While this approach is efficacious from a corneal ectasia treatment standpoint, procedures that involve removal of the epithelium can be associated with development of dry eye symptoms owing to disruption of sensory input to the lacrimal gland from the corneal epithelial nerves [4]. Similar changes have been described following refractive procedures such as LASIK and photorefractive keratectomy (PRK), which has led to interest in perioperative treatment of dry eye disease for patients undergoing procedures involving the surface of the cornea [5].

The treatment of dry eye has undergone major innovation over the last decade including the introduction of new topical agents and treatments specifically targeted to meibomian gland dysfunction [6‐8]. This expansion of treatment options has allowed providers to tailor their approach to the treatment of dry eye based on the perceived or known underlying etiology. Neurostimulation is a another relatively new category of treatment options that promotes natural tear production [9]. Furthermore, neurostimulation avoids the concerns associated with topical medications, which have well-established issues with drop adherence and instillation, as well as potential adverse influences on healing of an epithelial defect or introduction of an infectious agent [10]. A novel neurostimulation pharmaceutical treatment option has recently been introduced, varenicline solution nasal spray, or VNS (Tyrvaya®, Viatris Inc). This treatment option, which employs a nasal spray containing a formulation of 0.03 mg of varenicline, stimulates an increase in basal tear production through activation of the trigeminal parasympathetic pathway and spares the ocular surface [11, 12].

Clinical trials leading to the approval of the VNS demonstrated that 28 days of twice-daily administration was safe and effective in reducing the signs and symptoms of dry eye disease (DED) [11, 13]. A follow-up trial demonstrated that VNS provides a sustained effect with favorable results out to approximately 3 months [12]. As mentioned, the importance of treating the ocular surface in patients undergoing procedures involving the surface of the cornea is well established by prior work [5, 14]. This study aimed to evaluate the use of the varenicline nasal spray in patients undergoing CXL, which involves removal of 9 mm of the central corneal epithelium to facilitate the treatment protocol.

This was a single-center, prospective, randomized, controlled, double-masked, two-arm, investigator-initiated clinical trial (NCT05136924). This study was reviewed and approved by the Western Institutional Review Board (WCG). All procedures conducted were in accordance with the WCG IRB and the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. Informed consent was obtained for each subject prior to the study.

For inclusion criteria, all participants in the study had to be between the ages of 18–50 and electing to undergo unilateral CXL surgery. All subjects had a diagnosed prior history of keratoconus or corneal ectasia without a history of ocular surface disease. Subjects were required to be willing and able to comply with clinic visits and have the ability to independently administer the study drug. Additional inclusion criteria included the following: best-corrected manifest refraction between 20/20 and 20/100, cessation of contact lens wear for ≥ 2 weeks prior to the CXL procedure and continued cessation until the end of the study. If a female subject was of childbearing potential, she had to use an acceptable means of contraception and have a negative urine pregnancy test at the baseline or screening visit.

For exclusion criteria, subjects with the presence of any concomitant corneal pathology that could interfere with the outcome of the CXL procedure were excluded. Subjects with the presence of any non-healing corneal epithelial defects or ulcers were excluded. Subjects with a history of temporary (within the past 1 month) or with current permanent punctal plugs were excluded. Subjects with any active infectious, ocular or systemic disease or with a history of intraocular inflammation were excluded. Subjects with a history of chronic or recurrent epistaxis, prior nasal or sinus surgery, nasal Continuous Positive Airway Pressure (CPAP) use or prior nasal pathology that would limit the use of the study drug were excluded. Patients with a history of prior blepharoplasty, corneal transplant or a systemic condition determined by the investigator to not be compatible with participation in the study were also excluded. Subjects with a known hypersensitivity to the study drug components were excluded. Subjects currently using a nicotinic acetylcholine receptor agonist (e.g., Chantix®) were also excluded.

Subjects were randomized into two groups in a 1:1 fashion following the screening visit, and the study aimed to enroll up to ten subjects in each arm. There were no dry eye parameters to guide inclusion in the study. All subjects underwent a battery of testing at baseline including tear break-up time (TBUT), which was subjectively measured by instilling a small amount of fluorescein into the eye and waiting for the first dry spot to appear without allowing the subject to blink. The length of time between the blink and the appearance of a dry spot was recorded as the TBUT. Both the physician performing the examination and the individual recording data were masked to treatment assignment. The study group was advised to use VNS twice daily for 28 days prior to the procedure and an additional 28 days following the procedure. The control arm was instructed to use the placebo (vehicle) nasal spray twice daily for the same time frame. All enrolled subjects underwent unilateral CXL using the Dresden protocol [2]. This protocol entails removal of the central epithelium (> 7 mm) followed by application of topical iso-osmotic riboflavin solution (0.1%) every 5 min for the duration of the procedure, which includes 30 min of ultraviolet-A (UVA) irradiation. Following the CXL procedure, a bandage contact lens (BCL) was placed. The BCL was scheduled to be removed at Day 7 but could be removed or kept in place based on healing of the cornea per discretion of the principal investigator.

Day 0 was the day of the CXL procedure and was denoted as the baseline visit for statistical comparison. Following the CXL procedure, subjects were evaluated at postoperative days 2 (48 h), 3 (72 h), 4 (96 h) and 7 (1 week). Following the 1-week visit, subjects returned for a 1-month postoperative visit, which occurred at day 28 (± 3 days). Subjects were monitored for adverse events at all visits.

Two questionnaires were administered in this study to evaluate patient-reported outcomes. All subjects completed the NEI VFQ-25, a 25-item questionnaire adapted from the National Eye Institute Visual Function Questionnaire (NEI-VFQ) that aims to assess the effect of visual impairment on a patient’s current health-related quality of life with questions related to symptoms of irritation both in and around the eye. The VFQ-25 is scored on a scale of 0–100 with 0 being the worst score and 100 being the best. This questionnaire was administered at baseline and again at days 7 and 28 following the procedure. The second questionnaire was the eye dryness score (EDS) with visual analog scale (VAS). The EDS aims to assess ocular comfort and dryness and is similarly scored on a scale of 0–100 with 0 implying extreme discomfort and dryness and 100 representing no discomfort with no dryness. The EDS was obtained at similar time points as the VFQ-25 and was administered at baseline and at days 7 and 28 following the procedure.

Twenty eyes were enrolled and completed the study, which included 8 eyes in the control arm and 12 eyes in the study arm. The baseline demographics are shown in Table 2.

The mean baseline NEI-VFQ-25 score was 71.9 ± 16.9 in the study group and 74.0 ± 18.3 in the control group. At day 7 (1 week), the change from baseline for the VFQ-25 was − 8.0 ± 13.0 (67.1 ± 15.1) in the study group and − 6.5 ± 21.1 (67.5 ± 19.0) in the control group. The between-group comparison was not statistically significant (p = 0.9). At day 28 (1 month), which represents the first primary endpoint, the change from baseline was − 0.1 ± 6.6 (75.1 ± 16.3) in the study group and − 1.6 ± 5.9 (72.4 ± 19.3) in the control group (p = 0.6). These results are summarized in Fig. 1.

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The mean percent resolution of the corneal epithelial defect was compared between the two groups within the first 7 days following the CXL procedure. At day 2, the mean resolution was 82.8% in the study group and 78.5% in the control group. At day 3, the mean resolution was 98.3% in the study group and 96.1% in the control group. By day 4, the mean resolution was 99.8% in the study group and 99.5% in the control group. At day 4, all but one eye achieved complete epithelial healing in the study group and control group. Overall, there was a faster complete resolution of epithelial healing in the study group; however, the between-group difference was not statistically significant at Days 2 or 3 (p > 0.05). These results are shown in Fig. 2.

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For EDS scores, the mean value at baseline was 23.9 ± 25.1 in the study group and 34.5 ± 25.9 in the control group. For change in EDS score, the mean change from baseline at day 7 was 1.5 + 20.4 (25.7 ± 13.9) in the study group and − 4.3 ± 27.2 (30.3 ± 20.1) in the control group (p = 0.8). At day 28, the mean change from baseline in the study group was − 8.3 ± 24.4 (14.7 ± 12.6) and was − 11.3 ± 22.6 (23.3 ± 20.3) in the control group (p ≤ 0.5). The between-group difference was not statistically significant at any time point.

For artificial tear usage, the mean number of times artificial tears were instilled at day 7 was 3.4 ± 3.3 in the study group and was 7.0 ± 3.2 in the control group (p ≤ 0.05). At day 28, the mean artificial tear daily use value was 1.4 ± 1.6 in the study group and was 4.1 ± 5.9 in the control group, but the between-group difference was not statistically significant (p = 0.2). By day 28, four subjects in the study arm were no longer using artificial tears.

Four adverse events were recorded overall, all in the study group. All were mild in severity and resolved without further sequelae. One subject had a persistent epithelial defect that responded to adjunctive topical therapies and healed without sequelae. Two incidences of epistaxis were reported by subjects but were isolated in nature and did not require intervention. One incidence of nausea was noted by the patient but resolved without intervention or sequelae.

To our knowledge, this represents the first study to evaluate the use of VNS to treat the signs and symptoms of dry eye disease following CXL, a procedure that involves removal of the corneal epithelium. Overall, although the results do not definitively favor the use of VNS versus placebo, this study demonstrates VNS could be a useful treatment option for patients following CXL for minimizing the signs and symptoms of dry eye. Furthermore, the results of this study also suggest that VNS may promote accelerated healing following CXL. In addition to these purported benefits, VNS also offers the benefit of sparing the ocular surface and minimizing the exposure of the ocular surface to preservatives or possible contaminants associated with use of topical drops.

Overall, the literature remains relatively limited regarding the impact of dry eye therapies or treatment options on rates of re-epithelialization and dry eye signs and symptoms following CXL. A study by Ozek et al. [15] evaluated the use of a topical formulation containing sodium hyaluronate and trehalose and found faster rates of healing following CXL comparing to drops containing sodium hyaluronate alone. Similar results were described by Kirgiz et al. [16] using autologous serum tears versus the conventional approach of liberal use of artificial tears. The use of a topical matrix therapy agent has also been studied in this population with encouraging results reported for improving rate of corneal epithelial healing [17]. The array of different options previously studied speaks to the importance of this topic and the importance of healing following epi-off CXL to minimize complications.

A similar study was performed and recently published in patients undergoing LASIK in which patients electing to undergo LASIK were treated with VNS for 3 months [18]. Similar to the findings reported in this study, there was not a statistically significant difference between the study and control groups favoring VNS. However, there were trends demonstrating directional improvement in dry eye parameters including fluorescein staining, Schirmer scores and tear osmolarity, suggesting that with a larger sample size there may have been a statistically significant difference. Nonetheless, this present study, although similar in design, evaluated the use of VNS following CXL, a procedure that involves removal of the corneal epithelium and thus different parameters were evaluated including rate of epithelial healing, an important aspect of recovery after CXL to minimize risk of infection and scarring.

In this study, there was not a statistically significant difference between the study and control groups in the primary or secondary outcome measures. However, there was a trend toward faster resolution of the epithelial defect in the study group by day 2 following the procedure. Although the difference was small and not statistically significant, it is possible that with an increased sample size, this numerical difference and trend toward faster resolution of healing in the study group may have been significantly different. It is also important to note this study enrolled subjects without a history of ocular surface disease or dry eye disease. Although VNS has been shown to be effective in patients regardless of stage of dry eye disease as evidenced by a recent study by Sheppard et al. [19], there has been no research to date evaluating the use of VNS in healthy subjects without a history of dry eye. This, in addition to the small sample size, likely contributed to the absence of a major benefit on subjective questionnaires such as the EDS or VFQ-25 employed in this study.

There are several potential complications following CXL with the most serious complication being a postoperative, vision-threatening infection or corneal ulcer. Although the incidence of infectious keratitis following CXL remains low [20], debridement of the corneal epithelium carries the theoretical risk of exposing the cornea to possible infection. Furthermore, delays in epithelial healing can lead to corneal melting, which has been reported in prior cases following CXL. Thus, resolution of corneal epithelial defect is an important parameter to monitor following any procedure involving removal of the corneal epithelium. In addition to topical antibiotics and steroids, artificial tears are widely used following procedures that involve removal of the corneal epithelium to accelerate corneal epithelial healing. Artificial tears are a good conservative option for topical lubrication and reducing friction to promote healing but carry limitations including those inherent to topical drops and risk of contamination [21, 22]. The use of VNS in this setting has the advantage of natural basal tear production and avoiding concerns with preservatives and possible contaminants. In addition, patients with an active epithelial defect may note discomfort with instillation of drops, and VNS avoids the ocular surface.

This study has several limitations. Most notably, there was a small sample size, and no sample size calculation was performed ahead of the study. Furthermore, mechanical stimulation of the anterior ethmoid nerve in the nasal mucosa by the saline in the control nasal spray can stimulate the trigeminal parasympathetic pathway; thus, results observed in the control group may be due to this potential mechanism. Despite these limitations, we believe the results of this study support further research and investigation with a larger study evaluating the perioperative use of VNS for promoting corneal healing and mitigating symptoms of dry eye after CXL.

This study demonstrates the potential value of VNS as an option for promoting corneal healing and minimizing the signs and symptoms of DED following CXL. Further study is needed to confirm these findings, but the results from this small study hold promise and at the very least support the use of VNS as an alternative to topical lubricants. The use of VNS carries obvious advantages compared to topical lubricants including avoidance of the ocular surface and potential exposure to possible contaminants and/or preservatives.