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Safety, adherence and discontinuation in varenicline solution nasal spray clinical trials for dry eye disease.

ABSTRACT: Aim: Herein, we report safety outcomes for varenicline solution nasal spray (VNS) within the context of clinical trial discontinuation, contrasting those with discontinuation outcomes from topical cyclosporine and lifitegrast clinical trials. Materials & methods: 1061 subjects were randomized across three clinical trials to receive either VNS 0.06 mg, VNS 0.03 mg, VNS 0.006 mg or vehicle control. Subjects who discontinued from treatment were noted and assigned to their appropriate categories. Results: Despite treatment emergent adverse events, 93.5% of subjects receiving VNS completed the treatment period. By comparison, only 80% of subjects in the integrated clinical trials for cyclosporine ophthalmic emulsion and 91% of subjects in the integrated trials for lifitegrast ophthalmic solution completed the full treatment period, respectively. Conclusion: In clinical trials, VNS demonstrated improvements in dry eye disease signs and symptoms, was well-tolerated, and had an overall completion rate >93%. Conventional dry eye treatments (e.g., cyclosporine and lifitegrast) noted considerably higher discontinuation rates in their clinical trials.

SUBMITTER: Hauswirth SG

PROVIDER: S-EPMC10402908 | biostudies-literature | 2023 Jun

REPOSITORIES: biostudies-literature

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Safety, adherence and discontinuation in varenicline solution nasal spray clinical trials for dry eye disease.

Hauswirth Scott G SG Kabat Alan G AG Hemphill Mandy M Somaiya Karan K Hendrix Laura H LH Gibson Andrea A AA

Journal of comparative effectiveness research 20230425 6

<b>Aim:</b> Herein, we report safety outcomes for varenicline solution nasal spray (VNS) within the context of clinical trial discontinuation, contrasting those with discontinuation outcomes from topical cyclosporine and lifitegrast clinical trials. <b>Materials & methods:</b> 1061 subjects were randomized across three clinical trials to receive either VNS 0.06 mg, VNS 0.03 mg, VNS 0.006 mg or vehicle control. Subjects who discontinued from treatment were noted and assigned to their appropriate ...[more]

PMID: 37096956

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Project description:BackgroundDry eye disease has a high prevalence and exerts a significant negative effect on quality of life. In China, there are currently no available nasal sprays to promote natural tear production in patients with dry eye disease. We therefore evaluated the efficacy and safety of OC-01 (varenicline solution) nasal spray versus vehicle in Chinese patients with dry eye disease.MethodsThis was a randomized, multicenter, double-masked, vehicle-controlled, phase 3 clinical trial conducted at ophthalmology departments in 20 hospitals across China (NCT05378945). Eligible patients had a diagnosis of dry eye disease based on patient symptoms, Eye Dryness Score (EDS), Schirmer's Test (with topical anesthesia) Score (STS), and corneal fluorescein staining (CFS) score. Participants were randomly assigned 1:1 using an Interactive Web Response System (IWRS) to receive OC-01 0.6 mg/mL twice daily (BID) or vehicle nasal spray. Participants, investigators, and sponsor were all masked to treatment assignment. The primary endpoint was the percentage of subjects in the intention-to-treat population achieving ≥10 mm improvement in STS from baseline at week 4.FindingsIn total, 340 patients were randomized from 21 July 2022 to 04 April 2023, 78.8% were female. Patients in the OC-01 group (n = 176) had significantly higher achievement of ≥10 mm improvement in STS (35.8% [n = 63] versus 17.7% [n = 29], stratified odds ratio: 2.67, 95% CI: 1.570-4.533, p = 0.0002) and a significantly greater increase from baseline STS (least-squares mean difference [SE]: 3.87 [0.794], p < 0.0001) at week 4 versus the vehicle group (n = 164). In addition, OC-01 led to a numerically greater reduction in mean EDS from baseline at week 4 compared to the vehicle group (LS mean [SE] difference: -1.3 [2.20]; 95% CI: -5.64 to 2.99, p = 0.5467). The most common adverse event was mild, transient sneezing (78% of OC-01 administrations). No serious adverse events related to nasal administration occurred.InterpretationOC-01 (varenicline solution) nasal spray BID has clinically meaningful efficacy for reducing the signs (as measured by STS) and may improve the symptoms (as measured by EDS) of dry eye disease, with an excellent safety and tolerability profile, in the Chinese population.FundingJixing Pharmaceutical Co. Ltd.

Project description:SignificanceThere is a clinical necessity for dry eye disease treatments that perform across a broad range of presenting patient severities. Varenicline solution nasal spray (VNS), a unique cholinergic agonist ocular surface-sparing nasal spray therapy, demonstrated significant improvement in both signs and symptoms of dry eye disease in subjects with mild, moderate, and severe symptoms as the clinical studies enrolled a more real-world patient population.PurposeThis study evaluated efficacy outcomes for VNS in patients with mild-moderate and severe dry eye disease.MethodsAn analysis of integrated data from two randomized clinical trials, ONSET-1 (NCT03636061) and ONSET-2 (NCT04036292) (vehicle control [VC], n = 294; VNS 0.03 mg, n = 308), was performed. Adults 22 years or older with dry eye disease, Ocular Surface Disease Index score of ≥23, corneal fluorescein staining score of ≥2 in ≥1 regions/≥4 all regions, and Schirmer Test Score (STS) of ≤10 mm (no restrictions on Eye Dryness Score [EDS]) were included in this study. Efficacy was evaluated using analysis of covariance among pre-specified subgroups of mild-moderate and severe baseline disease severity defined by STS (≤5 vs. >5) and EDS (<60 vs. ≥60). Consistency of effect was evaluated by interaction tests.ResultsNo treatment-subgroup interactions were observed for all end points ( P > .05). The odds of achieving a ≥10-mm improvement in STS for VNS versus VC for patients with baseline STS ≤5 and >5 were 3.4(95% confidence interval, 2.0 to 5.6) and 2.3(1.3 to 4.0) and for EDS of <60 and ≥60 were 3.4(1.9 to 6.1) and 2.5(1.5 to 4.0). Least-squares mean treatment/VC differences in change from baseline in EDS for patients with baseline STS ≤5 or >5 were -7.4(95% confidence interval, -12.5 to -2.4) and -2.8(-8.7 to 3.1); EDS of <60 and ≥60 were -2.9(-8.3 to 2.5) and -8.1(-13.6 to -2.6).ConclusionsCompared with VC, VNS improved tear production and patient-reported symptoms in patients with dry eye disease, demonstrating consistency of effect regardless of initial presenting severity.

Project description:IntroductionThis study sought to compare the efficacy of OC-01 (varenicline solution) nasal spray for treatment of dry eye disease (DED) in postmenopausal women (PM+) versus women who were not postmenopausal (PM-).MethodsThis was a post hoc subgroup analysis of data integrated from two prior randomized controlled clinical trials, ONSET-1 and ONSET-2. Women randomized to treatment with OC-01 (varenicline solution) nasal spray 0.03 mg or vehicle control (VC) whose self-reported menopausal status (PM+ versus PM-) was known were included. Outcomes included the treatment difference (the OC-01 [varenicline solution] nasal spray change from baseline [CFB] minus VC CFB) in Schirmer test score (STS, mm) with anesthesia and the eye dryness score (EDS) measured on a 100-mm visual analog scale (0 = no discomfort, 100 = maximal discomfort). Least-squares mean treatment differences were derived from analysis of covariance (ANCOVA) models.ResultsOverall, 449 female participants in the ONSET-1 and ONSET-2 trials randomized to the OC-01 (varenicline solution) nasal spray 0.03 mg or VC groups were included in this analysis. The treatment-menopausal status interaction terms in the STS and EDS ANCOVA and logistic regression models were not statistically significant (p > 0.05), indicating consistency of treatment effect between the PM- and PM+ groups. The treatment difference in STS was similar in the PM- and PM+ groups (6.7 and 5.5 mm, respectively). The treatment difference in EDS was similar in the PM- and PM+ groups (- 5.5 and - 4.1, respectively).ConclusionsOC-01 (varenicline solution) nasal spray demonstrated similar efficacy in promoting natural tear production and improving symptoms in both PM- and PM+ groups. As menopausal-related hormonal changes may be associated with more severe DED, these results may support OC-01 (varenicline solution) nasal spray as an effective treatment for DED in women regardless of presenting menopausal status.Trial registrationPost hoc subgroup analysis of data integrated from ONSET-1 (ClinicalTrials.gov identifier NCT03636061) and ONSET-2 (ClinicalTrials.gov identifier NCT04036292).

Project description:IntroductionDry eye disease is characterized by a persistently unstable or deficient tear film causing discomfort or visual impairment. Varenicline is a small-molecule nicotinic acetylcholine receptor agonist recently approved for use as a preservative-free nasal spray (OC-01 [varenicline solution] nasal spray [OC-01 VNS]) to treat signs and symptoms of dry eye disease, but its effect on conjunctival goblet cells has not been studied.MethodsIn this phase 2, single-center, vehicle-controlled study, patients aged 18 years or more with a diagnosis of dry eye disease and Ocular Surface Disease Index© score of at least 23 were randomized 2:1 to receive a 50-µL single dose of OC-01 0.06 mg VNS or vehicle nasal spray in each nostril. Image assessments for area and perimeter were performed pre and 10 min post treatment for goblet cells by in vivo confocal microscopy and for meibomian glands by infrared meibography. Non-parametric Wilcoxon signed-rank test compared pre- and post-treatment measurements for each treatment group. Treatment-emergent adverse events (TEAEs) were assessed.ResultsThe study randomized 18 patients (mean age 61 years); 6 received vehicle (3/6 [50%] female) and 12 patients received OC-01 VNS (11/12 [92%] female). OC-01 VNS treatment decreased mean goblet cell area (pre-treatment, 106.4 µm2; post-treatment, 67.6 µm2; p = 0.02) and perimeter (pre-treatment, 38.9 µm; post-treatment, 31.2 µm; p = 0.03) but not vehicle did not (p = 0.25). There were no significant changes in mean meibomian gland area with either treatment (p ≥ 0.05). All TEAEs were non-ocular, non-serious, and mild.ConclusionsThis study demonstrated that a single administration of OC-01 0.06 mg VNS in patients with dry eye disease reduced conjunctival goblet cell area and perimeter, suggesting goblet cell degranulation and associated release of lubricating mucin. By activating the natural tear film, OC-01 VNS may provide benefits over topical medications.Trial registrationClinicalTrials.gov, NCT03688802.

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Safety, adherence and discontinuation in varenicline solution nasal spray clinical trials for dry eye disease.

Publications

Safety, adherence and discontinuation in varenicline solution nasal spray clinical trials for dry eye disease.

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