Clinical and Biological Evaluation of NAAGA Versus Azelastine Eye Drops in Allergic Subjects With Tear Film Dysfunction

Phase 4

Completed

• Conditions: Allergic Conjunctivitis; Dry Eye Disease (DED)
• Interventions: Drug: NAAGA (N-acetyl-aspartyl-glutamate) 49 mg/mL; Drug: azelastine hydrochloride 0.05%

• Registration Number: NCT06800274
• Lead Sponsor: Azienda Ospedaliera OO.RR. S. Giovanni di Dio e Ruggi D'Aragona

Brief Summary

This randomized, single-blind study aims to compare the efficacy and safety of N-acetyl-aspartyl-glutamate (NAAGA) and azelastine hydrochloride eye drops in patients with allergic conjunctivitis associated with tear film dysfunction. A total of 134 atopic patients with mild-to-moderate tear film dysfunction were included. Participants were randomly assigned to receive either NAAGA (49 mg/mL, four times daily) or azelastine (0.05%, twice daily) for four weeks. The primary endpoint is the change in Ocular Surface Disease Index (OSDI) scores from baseline to week 4. Secondary endpoints include tear osmolarity, Schirmer test results, tear break-up time (TBUT), MMP-9 levels, and corneal staining scores. This study seeks to provide evidence for the tailored management of allergic conjunctivitis and tear film dysfunction.

Detailed Description

There is limited but growing evidence in the literature regarding the effectiveness of N-acetyl-aspartyl-glutamate (NAAGA) in managing allergic conjunctivitis, particularly in patients with concomitant tear film dysfunction. NAAGA is a neuropeptide with dual activity as a mast cell stabilizer and anti-inflammatory agent, reducing histamine release and mitigating inflammatory cascades such as leukotriene production and complement activation. These mechanisms address both the allergic and inflammatory components of ocular surface diseases. Despite its promising therapeutic potential, studies directly comparing NAAGA to other treatments, particularly H1 receptor antagonists like azelastine, remain scarce.

In previous studies, NAAGA has demonstrated efficacy in reducing ocular surface inflammation, improving tear film stability, and alleviating symptoms of dry eye disease (DED). It has been reported a significant reduction in inflammatory markers, such as HLA-DR expression, and improvement in tear break-up time (TBUT) and Ocular Surface Disease Index (OSDI) scores in patients treated with NAAGA. Another investigation comparing NAAGA to cyclosporine A noted faster symptom relief and fewer adverse effects with NAAGA, highlighting its tolerability and potential for broader application. However, the literature lacks robust, head-to-head comparisons of NAAGA with second-generation antihistamines, such as azelastine, in the context of allergic conjunctivitis with tear film dysfunction.

Based on this background, this randomized, single-blind trial is designed to compare the efficacy and safety of NAAGA (49 mg/mL) with azelastine hydrochloride (0.05%) in treating patients with mild-to-moderate allergic conjunctivitis associated with tear film dysfunction. Both treatments target key mechanisms of disease but differ in their primary mode of action. NAAGA offers dual anti-inflammatory and mast cell-stabilizing effects, while azelastine acts predominantly as an H1 receptor antagonist with additional mast cell stabilization.

The primary objective of this study is to demonstrate that NAAGA is non-inferior to azelastine in improving symptoms and clinical parameters of allergic conjunctivitis associated with tear film dysfunction. Specifically, the study will evaluate changes in the Ocular Surface Disease Index (OSDI) score over four weeks of treatment. Secondary objectives include assessing changes in tear osmolarity, TBUT, Schirmer test results, MMP-9 levels, and corneal staining scores, as well as patient-reported symptoms of ocular discomfort.

This trial will include 134 patients with atopy and mild-to-moderate tear film dysfunction, randomized to receive either NAAGA eye drops (administered four times daily) or azelastine eye drops (administered twice daily) for four weeks. Both groups will undergo comprehensive evaluations, including the OSDI questionnaire, tear osmolarity testing, Schirmer I test, TBUT measurement, MMP-9 assessment, and fluorescein staining of the ocular surface. Patient-reported discomfort will be tracked through weekly diaries.

The investigation is expected to provide critical insights into the comparative efficacy and safety of NAAGA and azelastine in this patient population. NAAGA's dual-action profile may offer broader therapeutic benefits, particularly in addressing inflammation-driven tear film instability and ocular surface damage. Results from this study could inform clinical decision-making and support the development of more targeted, personalized treatments for patients with allergic conjunctivitis and tear film dysfunction.

Study Timeline

• Study Start: 2023-04-21
• Primary Completion: 2024-03-28
• Study Completion: 2024-03-28
• Study First Submitted: 2025-01-23
• Study First Submitted QC: 2025-01-23
• Study First Posted: 2025-01-29
• Status Verified: 2025-07
• Last Update Submitted: 2025-07-10
• Last Update Posted: 2025-07-15

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 134

Inclusion Criteria

• Adults (≥18 years) with atopy confirmed by skin prick tests, elevated specific IgE levels, or Prist result >100 kU/L.
• Mild-to-moderate tear film dysfunction defined by OSDI scores ≥13 and at least one diagnostic abnormality (TBUT <10 sec, Schirmer I test <10 mm, CLEK score for corneal staining >1, or tear osmolarity >308 mOsm/L).

Exclusion Criteria

• Severe ocular surface disorders

• Unilateral dry eye syndrome.

• Recent ocular surgery (within 3 months) or refractive surgery (within 6 months).

  . - Active ocular infections.

• Previous herpetic keratitis.

• Systemic or topic therapies with steroids in the last three months.

• Local therapies in the last 14 days.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
NAAGA Group	NAAGA (N-acetyl-aspartyl-glutamate) 49 mg/mL	-
Azelastine Group	azelastine hydrochloride 0.05%	-

Primary Outcome Measures

Name	Time	Method
Improvement in Ocular Surface Disease Index (OSDI) Score from Baseline	Week 4	The OSDI is a validated questionnaire used to measure the severity of dry eye disease and its impact on vision-related quality of life. It includes 12 questions divided into three subscales: ocular symptoms, vision-related functions, and environmental triggers. Each item is scored on a scale from 0 ("none of the time") to 4 ("all of the time"). The total OSDI score is calculated on a scale of 0 to 100, with higher scores indicating greater severity. A clinically meaningful change is defined as a decrease of ≥10 points.

Secondary Outcome Measures

Name	Time	Method
Reduction in MMP-9 Positivity from Baseline	Week 4	Inflammation will be assessed using the InflammaDry® test to detect matrix metalloproteinase-9 (MMP-9) levels in tear fluid. MMP-9 is an inflammatory marker elevated in dry eye disease. Results will be reported as positive or negative.
Improvement in OSDI Score from Baseline	Week 2	The OSDI score, as described above, will also be evaluated at an intermediate time point to track early symptom relief. The total OSDI score is calculated on a scale of 0 to 100, with higher scores indicating greater severity. A clinically meaningful change is defined as a decrease of ≥10 points.
Changes in Tear Osmolarity from Baseline	Week 2 and Week 4	Tear osmolarity will be measured using a TearLab osmometer. Tear samples will be collected from the inferior tear meniscus, and osmolarity will be expressed in mOsm/L. Elevated tear osmolarity (\>308 mOsm/L) is a hallmark of dry eye disease. A reduction in tear osmolarity reflects improved tear film stability and reduced ocular surface stress.
Improvement in Tear Break-Up Time (TBUT) from Baseline	Week 2 and Week 4	The TBUT will be measured using fluorescein dye and a cobalt-blue filtered slit lamp. The time from the last blink to the first visible break in the tear film will be recorded in seconds. Two readings will be averaged unless they differ by more than 2 seconds, in which case a third reading will be included. TBUT values of less than 10 seconds indicate tear film instability.
Improvement in Schirmer's Test 1 Results from Baseline	Week 2 and Week 4	The Schirmer's test will measure total tear production, including both basal and reflex tearing. A 35 mm x 5 mm strip of filter paper will be placed in the lower conjunctival sac for 5 minutes. The length of wetting in millimeters will be recorded. A normal value is considered \>10 mm in 5 minutes, while dry eye is diagnosed at \<5 mm.
Improvement in Corneal Staining Scores	Week 4	Corneal staining will be evaluated using fluorescein dye and the National Eye Institute (NEI)/Industry Workshop guidelines. The cornea will be divided into five regions (central, superior, inferior, nasal, and temporal), with each region graded on a 0-3 scale, yielding a total score of 0-15. Higher scores indicate more severe staining and damage.
Patient-Reported Changes in Ocular Discomfort	Week 4	Participants will maintain weekly symptom diaries to report ocular discomfort. Scores will be evaluated on a 5-point Likert scale, with higher scores indicating greater symptom severity.
Incidence of Treatment-Emergent Adverse Events (TEAEs)	Week 4	Safety and tolerability will be assessed by recording the incidence and nature of treatment-emergent adverse events (TEAEs), serious adverse events (SAEs), adverse device effects (ADEs), and serious ADEs (SADEs) throughout the study. Investigational Medical Device Deficiencies (IMDDs) will also be tracked.

Trial Locations

Locations (1)

Azienda Ospedaliera Universitaria OO.RR. S. Giovanni di Dio e Ruggi D'Aragona; 🇮🇹 Salerno, Italy