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Allergic ConjunctivitisPhase 4NCT06800274

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

A Phase 4 study testing NAAGA (N-acetyl-aspartyl-glutamate) 49 mg/mL and azelastine hydrochloride 0.05% in people with Allergic Conjunctivitis and Dry Eye Disease (DED), run by Azienda Ospedaliera OO.RR. S. Giovanni di Dio e Ruggi D'Aragona at 1 site in Italy.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
Search all trials

Trial 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. Read more about this study

Who is it for?
Ages 18 years and older
What is being tested?
NAAGA (N-acetyl-aspartyl-glutamate) 49 mg/mL and azelastine hydrochloride 0.05%
Could I receive a placebo?
No, everyone receives an active treatment
How many people
134 participants
Where
1 siteItaly
Study dates
21 Apr 2023to 28 Mar 2024
Phase
Phase 4
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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).

Who cannot join

  • 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.

Trial locations and contacts

1 site in 1 country.

Italy1 site

  • Azienda Ospedaliera Universitaria OO.RR. S. Giovanni di Dio e Ruggi D'Aragona

    Salerno, Salerno, 84131

Other trials in Italy

About this study

Official title: A Randomized, Single-Blind Clinical Investigation to Compare the Efficacy and Safety of N-Acetyl-Aspartyl-Glutamate (NAAGA) Versus Azelastine Eye Drops in Patients With Allergic Conjunctivitis Associated With Tear Film Dysfunction

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.

Read the 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.

Being tested
NAAGA (N-acetyl-aspartyl-glutamate) 49 mg/mL, azelastine hydrochloride 0.05%
Keywords
allergic conjunctivitis, dry eye disease (DED), tear film dysfunction, azelastine, antihistamine eye drops, N acetyl-aspartyl glutamic acid (NAAGA)
Medical subject headings
Conjunctivitis, Allergic, Dry Eye Syndromes

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • NAAGA (N-acetyl-aspartyl-glutamate) 49 mg/mLDrug

    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.

  • azelastine hydrochloride 0.05%Drug

    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.

Study groups in NCT06800274
Study groupRoleWhat they receive
NAAGA GroupExperimentalNot described
Receives: Drug: NAAGA (N-acetyl-aspartyl-glutamate) 49 mg/mL
Azelastine GroupActive comparatorNot described
Receives: Drug: azelastine hydrochloride 0.05%

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. 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.

    Measured: Week 4

Secondary outcomes (8)

  1. 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.

    Measured: Week 2

  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.

    Measured: Week 2 and Week 4

  3. 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.

    Measured: Week 2 and Week 4

  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.

    Measured: Week 2 and Week 4

  5. 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.

    Measured: Week 4

  6. 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.

    Measured: Week 4

  7. 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.

    Measured: Week 4

  8. 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.

    Measured: Week 4

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted29 Jan 2025
  2. Study start21 Apr 2023
  3. Primary completion28 Mar 2024
  4. Study completion28 Mar 2024

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 4
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Masking
None (open label)
Enrolment
134 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT06800274
Sponsor's protocol ID
ASL Napoli 3 sud n. 31/2019
Status last verified
Jul 2025
First submitted
23 Jan 2025
Last updated
15 Jul 2025
Results posted
No
Data monitoring committee
No
FDA-regulated drug
No
FDA-regulated device
No
Individual data sharing
Yes

Publications

  • Suarez-Cortes T, Merino-Inda N, Benitez-Del-Castillo JM. Tear and ocular surface disease biomarkers: A diagnostic and clinical perspective for ocular allergies and dry eye disease. Exp Eye Res. 2022 Aug;221:109121. doi: 10.1016/j.exer.2022.109121. Epub 2022 May 21.

    PubMed 35605673

  • Shin D, Sang Min J. Comparison of treatment effects between 4.9% N-acetyl-aspartyl glutamic acid and 0.05% cyclosporine A eye drops in dry eye patients. Graefes Arch Clin Exp Ophthalmol. 2022 Oct;260(10):3285-3291. doi: 10.1007/s00417-022-05682-x. Epub 2022 Apr 29.

    PubMed 35486175

  • Regu VR, Swain RP, Subudhi BB. Drug Delivery for Ocular Allergy: Current Formulation Design Strategies and Future Perspectives. Curr Pharm Des. 2023;29(33):2626-2639. doi: 10.2174/0113816128275375231030115828.

    PubMed 37936454

  • Leonardi A, Quintieri L, Presa IJ, LLoves JM, Montero J, Benitez-Del-Castillo JM, Leston FJS, Gonzalez-Mancebo E, Asero R, Groblewska A, Kuna P. Allergic Conjunctivitis Management: Update on Ophthalmic Solutions. Curr Allergy Asthma Rep. 2024 Jul;24(7):347-360. doi: 10.1007/s11882-024-01150-0. Epub 2024 Jun 13.

    PubMed 38869807

  • Kumar N, Feuer W, Lanza NL, Galor A. Seasonal Variation in Dry Eye. Ophthalmology. 2015 Aug;122(8):1727-9. doi: 10.1016/j.ophtha.2015.02.013. Epub 2015 Apr 6. No abstract available.

    PubMed 25912217

  • Janeczko P, Norris MR, Bielory L. Assessment of receptor affinities of ophthalmic and systemic agents in dry eye disease. Curr Opin Allergy Clin Immunol. 2021 Oct 1;21(5):480-485. doi: 10.1097/ACI.0000000000000773.

    PubMed 34387278

  • James IG, Campbell LM, Harrison JM, Fell PJ, Ellers-Lenz B, Petzold U. Comparison of the efficacy and tolerability of topically administered azelastine, sodium cromoglycate and placebo in the treatment of seasonal allergic conjunctivitis and rhino-conjunctivitis. Curr Med Res Opin. 2003;19(4):313-20. doi: 10.1185/030079903125001785.

    PubMed 12841924

  • Jambou D, Lapalus P. Effect of N-acetyl-aspartyl-glutamate (Naaga) on in-vitro leukotriene synthesis by macrophage cell line P388D1. Int J Tissue React. 1990;12(5):273-80.

    PubMed 1983004

  • Herrero-Vanrell R, Jauregui Presa I, Leceta Bilbao A, Montero-Iruzubieta J. Fundamental Aspects and Relevance of Components in Antihistamine Eye Drops. J Investig Allergol Clin Immunol. 2023 Dec;33(6):431-438. doi: 10.18176/jiaci.0963.

    PubMed 38095492

  • Goldschmidt PL, Vulliez-Le Normand B, Briquet I, Dray F. Effects of N-acetyl-aspartyl glutamic acid and sodium cromoglycate on leukotriene B4 secretion by human leukocytes. Allergy. 1990 Jul;45(5):363-9. doi: 10.1111/j.1398-9995.1990.tb00512.x.

    PubMed 2165751

  • Garcia-Queiruga J, Pena-Verdeal H, Sabucedo-Villamarin B, Garcia-Resua C, Giraldez MJ, Yebra-Pimentel E. Temporal Progression of Entry Factors into the Vicious Circle of Dry Eye in Untreated Sufferers. Life (Basel). 2024 Jun 26;14(7):806. doi: 10.3390/life14070806.

    PubMed 39063561

  • Fukuda K, Kishimoto T, Sumi T, Yamashiro K, Ebihara N. Biologics for allergy: therapeutic potential for ocular allergic diseases and adverse effects on the eye. Allergol Int. 2023 Apr;72(2):234-244. doi: 10.1016/j.alit.2022.09.005. Epub 2022 Nov 1.

    PubMed 36333219

  • El Fekih L, Khairallah M, Ben Amor H, Mahmoud A, Chiambaretta F, Messaoud R. Successful management of dry eye disease with a new eye drop formulation combining hyaluronic acid, trehalose, and N-acetyl-aspartyl-glutamic acid (NAAGA). J Fr Ophtalmol. 2024 Sep;47(7):104169. doi: 10.1016/j.jfo.2024.104169. Epub 2024 Jun 4.

    PubMed 38838456

Questions about this trial

What is this clinical trial studying?

A Phase 4 study testing NAAGA (N-acetyl-aspartyl-glutamate) 49 mg/mL and azelastine hydrochloride 0.05% in people with Allergic Conjunctivitis and Dry Eye Disease (DED), run by Azienda Ospedaliera OO.RR. S. Giovanni di Dio e Ruggi D'Aragona at 1 site in Italy.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 2 inclusion and 7 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 15 Jul 2025. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in Italy. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Improvement in Ocular Surface Disease Index (OSDI) Score from Baseline (time frame: Week 4). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT06800274, which also lists 13 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 15 Jul 2025.

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