Effect of Topical Antioxidants in Dry Eye Disease and Diabetic Retinopathy

Study Overview
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Brief Summary
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The main objective of our study is to evaluate the effect of eye drops with antioxidants on mild to moderate dry eye symptoms in patients with diabetic retinopathy, evaluating the levels of inflammatory cytokines and oxidative stress in the tear film. The researchers intend to include 78 patients, divided into three intervention groups, who will be randomly assigned an eye drop with antioxidants, where the patient must apply one drop in each eye for 1 month. In the study, the characteristics of the surface of the eye will be evaluated and tear samples will be taken from each eye, before and after the intervention with the eye drops. Subsequently, the clinical and sample results will be evaluated to compare the effects between them.

Detailed Description
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Dry eye syndrome is a multifactorial disease where tear film homeostasis is lost, accompanied by ocular symptoms such as burning, blurred vision, foreign body sensation, ocular redness, itching, in which tear film instability and hyperosmolarity, causing inflammation of the ocular surface, endothelial damage and neurosensory alterations. Worldwide, in patients with diabetic retinopathy it has a prevalence of 54%, however in Mexico, only a prevalence of 41% has been described in the diabetic population, without having reports of prevalence in patients with diabetic retinopathy. The state of chronic hyperglycemia in diabetes mellitus causes neuropathic corneal damage and dysfunction of the meibomian glands, this promotes a decrease in tear production, establishing dysfunction of the tear film and a state of hyperosmolarity in it, the latter induces activation of inflammatory mediators and release of proinflammatory cytokines that generate more damage to the corneal surface, entering a vicious cycle of tear film instability. Likewise, the preexisting state of oxidative stress in patients with diabetic retinopathy, where there is an imbalance between the production and degradation of reactive oxygen species, contributes to the induction of changes in the corneal surface and tear film dysfunction. Dry eye treatment is focused on the characteristics of the tear film and the characteristics of the ocular surface, with the aim of controlling and improving symptoms, with the use of different formulations and tolerability profiles. However, these are not adequate to reduce the effect of the inflammatory state and oxidative stress present in the tear film and the ocular surface, causing the patient's visual quality to worsen. The researchers intend to assess whether antioxidant therapy in eye drops influences levels of oxidative stress and inflammatory markers in the tear film.

Official Title
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Effect of Combined Antioxidant Therapy in Eye Drops on Inflammatory and Oxidative Stress Biomarkers in Tear Film in Patients With Diabetic Retinopathy and Dry Eye Syndrome

Conditions
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Dry Eye Syndromes, Diabetic Retinopathy, Oxidative Stress, Tear Film Deficiency

Intervention / Treatment
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* Drug: VisuXL®
* Drug: Lagricel PF®
* Drug: Humylub PF®


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with type 2 diabetes, with presence of diabetic retinopathy in any of its stages without data on severity Patients who voluntarily give their informed consent. Patients who meet an Ocular Surface Disease Index (OSDI) score between 13-32 points (mild to moderate severity) Patients who meet one or more of the following: Tear film breakup time equal to or less than 10 seconds Corneal fluorescein staining with more than 5 sites Conjunctival staining with more than 9 sites. Non-smokers or history of inactive smoking > 6 months Metabolic criteria: Glycated hemoglobin equal to or less than 9% LDL less than or equal to 100 mg/dl Triglycerides less than or equal to 180 mg/dl Blood pressure less than or equal to 140/80 mm Hg Exclusion Criteria: Patients with autoimmune diseases and/or Sjögren's disease Patients with neurodegenerative processes and/or cancer Present aggregate ophthalmological diagnosis of: Glaucoma Allergic, viral or bacterial conjunctivitis. Demodex Eye parasitic infections. Unresolved eye trauma Scarring diseases of the ocular surface Corneal or conjunctival ulcers. Filamentous keratitis, neurotrophic Bullous keratopathy Patients taking any of the following medications: Osmotic diuretics Alpha agonists NSAIDs, cannabinoids or opioids Benzodiazepines, selective serotonin reputate inhibitors, monoamine oxidate inhibitors nonlepromatous, antimalarials (Chloroquine / Hydroxychloroquine) Corticosteroids

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Clinical trial phase 2 A.
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Q10 coenzyme, vitamin E and cross-linked hyaluronic acid<br>This arm will administer eye drops with a combination of cross-linked hyaluronic acid, Q10 coenzyme and vitamin E, it will consist of 26 patients with diabetic retinopathy and mild to moderate dry eye syndrome. One drop will be instilled in each eye every 4 hours for a month. | Drug: VisuXL®<br>* It consists of a preservative-free eye drop composed of 100 mg cross-linked hyaluronic acid, 100 mg coenzyme Q10, 500 mg vitamin E TPGS (D-alpha-tocopheryl polyethylene glycol succinate), one drop is applied in each eye every 4 hours for a month.<br>* Other names: VisuXL tear drop;|
| Active Comparator: Sodium hyaluronate<br>This arm will administer eye drops with sodium hyaluronate, it will consist of 26 patients with diabetic retinopathy and mild to moderate dry eye syndrome. One drop will be instilled in each eye every 4 hours for a month. | Drug: Lagricel PF®<br>* It consists of a preservative-free eye drop composed of sodium hyaluronate 0.4%, one drop is applied in each eye every 4 hours for a month.<br>* Other names: Lagricel preservative free;|
| Active Comparator: Sodium hyaluronate and chondroitin sulfate<br>This arm will administer eye drops with a combination of sodium hyaluronate and chondroitin sulfate, it will consist of 26 patients with diabetic retinopathy and mild to moderate dry eye syndrome. One drop will be instilled in each eye every 4 hours for a month. | Drug: Humylub PF®<br>* It consists of eye drops without preservatives composed of 0.1% sodium hyaluronate and 0.18% chondroitin sulfate, one drop is applied to each eye every 4 hours for a month.<br>* Other names: Humylub preservative free;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline in levels of tumor necrosis factor alpha (TNF-a) in tear film at 30 days. | Tears will be collected with Drummond glass® micro capillary tubes without stimulation of tear secretion and placed in an eppendorf tube at -80 celsius degrees. The cytokine concentration will be determined with multiplex bead immunoassays technique and reported in picogram per milliliter units (pg/mL) | 30 days | 
| Change from baseline in levels of interleukin 8 (IL-8) | Tears will be collected with Drummond glass® micro capillary tubes without stimulation of tear secretion and placed in an eppendorf tube at -80 celsius degrees. The cytokine concentration will be determined with multiplex bead immunoassays technique and reported in picogram per milliliter units (pg/mL) | 30 days | 
| Change from baseline in levels of interleukin 6 (IL-6) | Tears will be collected with Drummond glass® micro capillary tubes without stimulation of tear secretion and placed in an eppendorf tube at -80 celsius degrees. The cytokine concentration will be determined with multiplex bead immunoassays technique and reported in pg/mL. | 30 days | 
| Change from baseline in levels of interleukin 10 (IL-10) | Tears will be collected with Drummond glass® micro capillary tubes without stimulation of tear secretion and placed in an eppendorf tube at -80 celsius degrees. The cytokine concentration will be determined with multiplex bead immunoassays technique and reported in picogram per milliliter units (pg/mL) | 30 days | 
| Changes from baseline in total antioxidant capacity in the tear film at 30 days. | Tears will be collected with Drummond glass® micro capillary tubes without stimulation of tear secretion and placed in an eppendorf tube at -80 celsius degrees. Total antioxidant capacity concentration will be determined with colorimetric assay technique and reported in units called Trolox equivalents (TE), nmol/sample. | 30 days | 
| Change from baseline in lipoperoxides levels in tear film at 30 days. | Tears will be collected with Drummond glass® micro capillary tubes without stimulation of tear secretion and placed in an eppendorf tube at -80 celsius degrees. Lipoperoxides concentration will be determined with colorimetric assay technique and reported in nmol/mL. | 30 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline in the pattern of ocular surface staining with fluorescein sodium according to Oxford Scheme at 30 days. | Ocular surface staining with fluorescein sodium dye it will be assessed during slit lamp examination and it will be measure on a scale from 0 to 5 according to the Oxford scheme, with 5 being the most severe staining. | 30 days | 
| Change from baseline in the pattern of ocular surface staining with lissamine green according to Oxford Scheme at 30 days. | Ocular surface staining with lissamine green dye it will be assessed during slit lamp examination and it will be measure on a scale from 0 to 5 according to the Oxford scheme, with 5 being the most severe staining. | 30 days | 
| Change from baseline in the tear break-up time (TBUT) in seconds at 30 days. | It will be measured the time interval in seconds between a complete blink and the first appearance of a dry spot in the tear film after fluorescein sodium administration during slit-lamp examination, considering less than 10 seconds as abnormal. | 30 days | 
| Change from baseline in tear film osmolarity at 30 days. | It will be measured collecting a tear sample in each eye with TearLab® Test reporting osmolarity in milliosmol per liter (mOsm/L) | 30 days | 
| Change from baseline in tear secretion in mm with Schirmer I test at 30 days. | Tear secretion will be assessed with a graduated test strip placed on the lower eyelid margin without anesthesia, after five minutes, the strip is removed and the amount of wetting is measured in mm, less than 10 mm is considered abnormal. | 30 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Dry Eye Disease, Oxidative Stress biomarkers, Inflammatory biomarkers, Tear film, Eye drops, Diabetic Retinopathy