A Phase 4 interventional study of NAAGA (N-acetyl-aspartyl-glutamate) 49 mg/mL and azelastine hydrochloride 0.05% in Allergic Conjunctivitis and Dry Eye Disease (DED), sponsored by Azienda Ospedaliera OO.RR. S. Giovanni di Dio e Ruggi D'Aragona. Completed at 1 site in Italy. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2025-07-15.
Sponsored by Azienda Ospedaliera OO.RR. S. Giovanni di Dio e Ruggi D'Aragona · Phase 4, Interventional, and Treatment
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.
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.
Exclusion Criteria:
Recent ocular surgery (within 3 months) or refractive surgery (within 6 months).
. - Active ocular infections.
Drug: NAAGA (N-acetyl-aspartyl-glutamate) 49 mg/mL
Drug: azelastine hydrochloride 0.05%
80 patients were randomly assigned to NAAGA in single dose (49 mg/mL), instilled as 1 drop per eye four times daily for four weeks. Specific diagnostic tests and procedures for dry eye disease were performed at week 0 (baseline), week 2 and week 4.
54 patients were randomly assigned to azelastine hydrochloride 0.05% instilled as 1 drop per eye 2 times a day in the conjunctival sac for for four weeks. Specific diagnostic tests and procedures for dry eye disease were performed at week 0 (baseline), week 2 and week 4.
Improvement in Ocular Surface Disease Index (OSDI) Score from Baseline
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.
Time frame: Week 4
Improvement in OSDI Score from Baseline
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.
Time frame: Week 2
Changes in Tear Osmolarity from Baseline
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.
Time frame: Week 2 and Week 4
Improvement in Tear Break-Up Time (TBUT) from Baseline
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.
Time frame: Week 2 and Week 4
Improvement in Schirmer's Test 1 Results from Baseline
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.
Time frame: Week 2 and Week 4
Reduction in MMP-9 Positivity from Baseline
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.
Time frame: Week 4
Improvement in Corneal Staining Scores
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.
Time frame: Week 4
Patient-Reported Changes in Ocular Discomfort
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.
Time frame: Week 4
Incidence of Treatment-Emergent Adverse Events (TEAEs)
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.
Time frame: Week 4
Plan to share: Yes
Supporting information: Study protocol, Sap, Csr
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Azienda Ospedaliera OO.RR. S. Giovanni di Dio e Ruggi D'Aragona