Multimodal Morpho-functional Study in Glaucoma Patients-Citicoline Oral Solution

Study Overview
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Brief Summary
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A prospective, multicentre, randomized, blinded, masked study that involves the enrollment of 60 patients affected by open angle glaucoma (OAG). Patients selected according to the inclusion / exclusion criteria, after signing the informed consent, will be randomized into two groups: In a group of patients with OAG, Citicoline in oral solution (10 ml / day, Neurotidine®) will be administered for 12 months (Citicoline Treated Group, TC Group) in another group of patients with OAG will be administered Placebo (Containing all excipients of Neurotidine ®) (10 ml / day) for 12 months (Placebo Treated Group, TP Group) Randomization will be done by dividing the selected patients into two groups based on similar characteristics of: age, perimetric defect and, mainly, retinal-cortical time (RCT) values. Patients will be assigned to each group by an investigator not involved in functional and structural testing. The key will be opened only at the end of the treatment in order to evaluate the first effects. The Primary Objective was to evaluate whether treatment with Citicoline in oral solution can produce an improvement of the post-retinal neural conduction, that is delayed in patients with OAG. The Secondary objective was to evaluate in patients with OAG whether the possible changes in post-retinal neural conduction induced by treatment with Citicoline in oral solution (information obtained through electrophysiological recordings) are associated or not with morphological and functional variations of the nervous structures forming the visual pathways (nucleus geniculatus lateral, optic tract, visual cortex, information obtained through the acquisition of structural and functional magnetic resonance imaging) and whether both conditions can be related to the morpho-functional variations of the retinal ganglion cells and of the visual field (VF).

Detailed Description
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Sixty patients affected by bilateral open angle glaucoma, between the ages of 20 and 70, will be enrolled in the study within a maximum time frame of 12 months. The enrollment will be performed at T0 (screening), in this occasion an extensive ophthalmological evaluation will be performed after the signature of the informed consent. The patient will be undergoing to the evaluation of Best corrected Visual Acuity (BCVA), intraocular pressure (IOP), fundus examination, Visual Field (VF) exam (Humphrey 24-2and 10-2 standard SITA) Visual Evoked Potentials (VEP) and pattern electroretinogram (PERG). Moreover a morphological examination of optic nerve and macular area was assessed by Optical Coherence Tomography (OCT) with the analysis of retinal nerve fiber layer (RNFL) and retinal ganglion cells (RGCs). Patients included in the study present a Mean Deviation defect (MD), tested at the VF examination, between -6 and -25 dB and an increase in Retinal-Cortical Time (RCT) response. RCT is a measure derived through the difference of Implicit Time values of latency of simultaneous recording of visual evoked potential (VEP) and pattern electroretinogram (PERG), which represent a post-retinal nerve conduction delay. About 7-15 days after T0 a new ophthalmological examination will be performed (T1). The patient will be undergoing to the evaluation of BCVA, IOP, fundus examination, VF exam (Humphrey 24-2and 10-2 standard SITA), VEP, PERG and OCT. In this occasion a Magnetic Resonance Imaging (MRI) of the brain will be performed. At the end of this evaluation, the patient will be given 4 bottles containing 500 ml of Citicoline in oral solution (Neurotidine®) or Placebo and will be given the relative instructions for administration. The posology will be 10 ml once a day in the morning for 6 months. At the end of the 6 month period the patient will be asked to hand over the used bottles. After 6 months ± 10 days, a novel complete ophthalmologic evaluation will be performed (T2) (BCVA, IOP, VF exam, VEP, PERG, OCT), and patients will be given an additional 4 bottles containing Neurotidine ® or Placebo and will be given instructions for their administration. Again at the end of this 6 month period the patient will bring back the used bottles. One year after T0, a last complete ophthalmological visit (BCVA, IOP, VF exam, VEP, PERG, OCT) will be performed (T3). In this visit MRI will be repeated. At the end of the visit, the patient will bring back the used bottles. Will be asked to the patient if adverse events will occurs during such period.

Official Title
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Modulation of Neuronal Connettivity Along the Visual Pathways in Patients Affected by Glaucoma Throug Treatment With Citicoline Oral Solution: Multimodal Morpho-funcional Study

Conditions
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Primary Open Angle Glaucoma

Intervention / Treatment
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* Dietary Supplement: Citicoline
* Dietary Supplement: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age between 20 and 70 years old Diagnosis of glaucoma. Glaucoma is defined as: glaucomatous damage of the CV (Humphrey 24-2 standard SITA with mean deviation between -6 and -25 dB) and glaucomatous appearance of the optic nerve Visual acuity not less than 5/10 Eye pressure below 21 mmHg with the use of ocular hypotonizing drugs including sympathomimetics, beta-blockers, prostaglandins, beta-adrenergics, carbonic anhydrase inhibitors. Such drugs can be used both alone and in combination with each other. Documented post-retinal nerve conduction delay through simultaneous recording of VEP and PERG showing an increase in RCT Exclusion Criteria: Ocular surgery in the 3 months preceding the study, including surgery for cataracts in the previous three months. Cataract or maculopathy Argon laser trabeculoplasty (ALT) within the previous 6 months Known hypersensitivity to the study product Secondary causes of ocular hypertension, including systemic or topical use of steroids Positive history of ocular or systemic diseases that could preclude enrollment in the study in the opinion of the investigators Changes in systemic therapies that could compromise intraocular pressure values (beta-blockers, alpha and beta adrenergics, calcium inhibitors, ACE inhibitors) in the 30 days prior to enrollment Ongoing therapy with vasoactive cerebral drugs, neurotrophic, lutein, zeaxanthin, retinal, acid, docosahexaenoic, Ubiquinone and / or its derivatives, Citicoline and / or its derivatives (possible previous treatment with Ubiquinone, L-Carnitine, Citicoline and / or its derivatives must have been suspended at least 6 months prior to inclusion in the study) Pregnancy, breastfeeding Diabetes Systemic lupus erythematosus, rheumatoid arthritis, connectivitis Concomitant use of anticoagulants and lithium

Ages Eligible for Study
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Minimum Age: 20 Years
Maximum Age: 70 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: Patients selected according to the inclusion / exclusion criteria, after signing the informed consent, will be randomized into two groups: In a group of patients with open angle glaucoma (OAG), Citicoline in oral solution (10 ml / day, Neurotidine®) will be administered for 12 months (Citicoline Treated Group, TC Group) in another group of patients with OAG will be administered Placebo (Containing all excipients of Neurotidine ®) (10 ml / day) for 12 months (Placebo Treated Group, TP Group)
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Citicoline Treated Group, TC Group<br>In a group of patients with open angle glaucoma (OAG), Citicoline in oral solution (10 ml / day) will be administered for 12 months (Citicoline Treated Group, TC Group) | Dietary Supplement: Citicoline<br>* The patient will be given 10 ml of Citicoline oral solution (Neurotidine ®) once a day in the morning for 1 year. To patients will be given 4 bottles containing 500 ml of Citicoline and the relative instructions for administration. After 6 months, the patient will bring back the used bottles and will be given additional 4 bottles containing Citicoline (Neurotidine ®). Again at the end of this 6 month period the patient will bring back the used bottles. Each bottle of Neurotidine will contain: water; fructose; Citicoline (500 mg per 10 ml); acidity regulators: sodium citrate, sodium hydroxide; preservative: potassium sorbate; dye: riboflavine.<br>|
| Placebo Comparator: Placebo Treated Group, TP Group<br>in another group of patients with open angle glaucoma (OAG) will be administered Placebo (Containing all excipients of Citicoline in oral solution) (10 ml / day) for 12 months (Placebo Treated Group, TP Group) | Dietary Supplement: Placebo<br>* The patient will be given 10 ml of an oral solution of Placebo. Each bottle of Placebo, the solution of which will be indistinguishable from the active product in terms of appearance and flavor, will contain: water; fructose; acidity regulators: sodium citrate, sodium hydroxide; preservative: potassium sorbate; dye: riboflavin<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Retino-cortical time (RCT) changes after treatment with citicoline in oral solution. | The changes of the retino-cortical time (RCT) in patients affected by open angle glaucoma after one years of treatment with Citicoline in oral solution compared to patients affected by open angle glaucoma treated with placebo. | One year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Correlation between RCT changes and morpho-functional parameters changes after treatment with citicoline in oral solution. | In patients with open angle glaucoma, the changes of retino-cortical time (RCT) are associated or not with morphological and functional changes in the nerve structures that form the optical pathways, measured by OCT (RNFL and RGCs), visual field (MD) and magnetic resonance, after one year of treatment with Citicoline in oral solution respect to patients treated with Placebo. | one year |