Citicoline Effect on Non-arteritic Anterior Ischemic Optic Neuropathy (NAION)
Citicoline Effect on Non-arteritic Anterior Ischemic Optic Neuropathy (NAION)
Clinical trial.gov

 Brief summary :

 Non-arteritic anterior ischemic optic neuropathy (NAION) is an optic neuropathy due to acute
 or subacute ischemic event of anterior optic nerve axons retrolaminar part that was
 vascularized by posterior ciliary brevis artery. The incidence of ischemia will be followed
 by axonal edema and causing compartment syndrome and heighten the incidence of ischemic.

 In NAION, the main pathology occurs at the level of the optical nerve, the axons of retinal
 ganglion cells. Initial damage is on the optic disc ischemia resulting hypoxic injury of
 axons and manifest as disc edema. Axonal edema cause disturbances of retrograde axonal
 transport of neurotrophic factors, especially brain derived neurotrophic factor, to the
 retinal ganglion cells. This will trigger a secondary toxicity and apoptosis. In addition,
 the presence of oxidative stress, calcium influx and mitochondrial damage will also triggers
 apoptosis. After the apoptosis of retinal ganglion cells, there was a thinning of the retinal
 nerve fiber layer (RNFL) through Wallerian degeneration. Thinning of the RNFL will manifest
 as visual field defects and the decline in visual acuity in patients with chronic phase
 NAION.

 Though NAION include disease entity that has long existed, but until now, there has been no
 evidence-based study on medical or surgical procedures that is effective enough to overcome
 NAION. The main treatment is to manage the risk factor such as hypertension, dyslipidemia,
 diabetes mellitus, hypercoagulable state. In general, if the patient is in the acute phase
 (edema of optic nerve head), methylprednisolone administration may be considered, but if the
 patient is already on chronic phase (atrophy disc) which generally occurs 6-11 weeks after
 the onset, then steroids are no longer indicated. Neuroprotective agent was considered as
 treatment in NAION given primary pathology NAION is the retinal ganglion cell axons. Among
 the various neuroprotective substance, Citidine diphosphocoline (CDP-choline
 5'-diphosphocholine or Citicoline) is a therapeutic option NAION.

 Citicoline is an endogenous mononucleotide consisting of ribose, cytosine, pyrophosphate, and
 choline. Citicoline is a component intermediates in the synthesis of phospholipids in cell
 membranes, ie phosphatidylcholine. Exogenous citicoline administered orally or intravenously,
 will be split into citidine and choline. Citicoline via oral administration can be absorbed
 completely and have a similar bioavailability in the blood compared to parenteral
 administration such as intravenous. Once absorbed, citicoline will be distributed throughout
 the body and enter the blood-brain barrier and the blood retinal barrier penetrate into the
 central nervous system. If there is damage to neurons, exogenous citicoline will participate
 in the synthesis of phospholipids in the neuronal cell membrane. Some studies show that
 citicoline may have a neuroprotective effect on retinal ganglion cells and supporting
 regeneration of damaged neurons in vitro. Previous research on the citicoline effect in
 chronic phase NAION give satisfactory results. Dopaminergic neurotransmitter systems known to
 occur in vast numbers in the retina and post-retinal visual pathway. Retinal ganglion cells
 using certain subtypes of dopamine as a means of communication with the visual cortex. Rejdak
 et al in animal models showed that citicoline administration could improve and strengthen the
 dopamine transmission in the retina. Citicoline also a safe medicine, without serious adverse
 effect.

 Electroretinogram (ERG) is a tool to measure the function of the retina. ERG examination can
 measure electrical changes in the retina after light stimulus. ERG examination that can
 detect changes in the activity of retinal ganglion cell is a pattern ERG. Spectral-domain
 optical coherence tomography is a tool that can measure the thickness of retinal ganglion
 cells.

 Thinning of the RNFL will manifest as visual field defects in patients with NAION. The
 typical visual field defects of NAION is altitudinal defects associated with segmental edema
 optic nerve head.

 Based on these descriptions question arises whether the citicoline supplementation can repair
 damage to the neurons of the retina, especially the retinal ganglion cells, in NAION
 resulting in improved retinal function which can be judged from the improvement of the value
 of the amplitude of the wave of P50 and N95 in the examination pattern ERG (PERG) when
 compared with placebo ? In addition whether citicoline supplementation can increase the
 thickness of retinal ganglion cells assessed using SD-OCT? Does citicoline supplementation
 give the effect of improving visual field defects in patients with NAION?
Research design This study is a double blind randomized clinical trial to determine
 differences in wave amplitude P50 and N95 on pattern ERG examination, visual field defects
 (LP) with Humphrey HFA (Humphrey Field Analyzer) II-i 750, 24-2 threshold and ganglion cell
 thickness with OCT CirrusTM between the administration of citicoline and placebo in patients
 with non-arteritic anterior ischemic optic neuropathy (NAION) chronic phase. Masking applied
 to patients and researchers.

 Research Time and Place This research was conducted at the Eye Clinic Division of
 Neuro-Ophthalmology Faculty of medicine Universitas Indonesia- RSCM (Cipto Mangunkusumo
 Hospital) Kirana (single centre), Jakarta, Indonesia in November 2016-June 2017.

 Population and Sample Research The target population of this study is that patients with
 chronic phase NAION. Samples were selected with consecutive sampling method, ie all NAION
 patients with chronic phase who came to the Faculty of medicine Universitas Indonesia-RSCM
 Kirana Neuro-ophthalmology division fulfilled the inclusion criteria included in the study
 and randomize by researchers. If the patient NAION was in acute phase, in the further visit
 became chronic phase and met the inclusion criteria, then the patient can be a sample.

 Inclusion criteria

 1. Patients aged 20-65 years.

 2. NAION patients who have been diagnosed clinically by a minimum of 1 consultant Division
 NO with onset ≥6 weeks.

 3. Best corrected visual acuity ≥ 1/60 Snellen

 4. Patients have to get an explanation about the purpose of the research and all the
 procedures that will be undertaken and willing to participate in the study by signing
 the informed consent.

 5. On bilateral NAION, examination of research done on one eye at a nearby onset of 6 weeks

 Exclusion criteria

 1. Haziness of refractive media, such as corneal opacities and opacities in the lens of
 moderate to severe (color and turbidity of the lens, the cortex and the posterior
 capsule with degrees LOCs (Lens Opacity Classification System) III> 3).

 2. Abnormalities in the macula and the optic disc due to causes other than NAION.

 3. Patients with a history of glaucoma.

 4. Patients with intraocular inflammation such as anterior and posterior uveitis.

 5. Taking antioxidant supplements or other neuroprotective agents in the last 2 weeks
 before randomization.

 6. Edema of optic nerve head condition detected clinically or by OCT. Dropout Criteria

 1. Patients which in the study drug administration period experienced NAION in the
 contralateral eye so requiring steroid therapy.

 2. Patients who experience severe side effects (headache, nausea, vomiting) that can not be
 resolved with symptomatic medication.

 Sample calculation The sample size was calculated based on previous studies that measure the
 amplitude of the wave N95 PERG in patients with NAION. From previous studies we obtained a
 standard deviation of 55% . The researchers set the value of minimal clinical differences
 were considered significant at 0.55.

 The sample size in this study was calculated based on the formula of the samples to test
 numerical analytic unpaired. Sample size was 16 people per group. Taking into account the
 drop out rate of 20%, is set to take a sample of 20 people for each treatment group (Group A:
 citicoline and group B : placebo) Subject allocation Subjects who have fulfilled the
 inclusion and exclusion criteria for the study were asked to sign an informed consent and
 will randomization. The allocation of the subject is done by using block randomization.
 Randomization will be performed by a third party before the study began. Number randomization
 results will be incorporated into the white envelope sealed and classified into group A (got
 citicoline) or group B (placebo) in accordance with the results of randomization.

 Examination and Intervention

 1. History taking, to obtain basic data about the patient's identity, course of the disease
 at this time, a history of previous disease (systemic and ocular), and history of
 previous treatment.

 2. Ophthalmological examination performed include:

 1. Examination of visual acuity using the Snellen chart for patients who can read or
 using Illiterate E chart for patients who can not read. Examination of visual
 acuity will be conducted refractionist of Department of Ophthalmology Faculty of
 medicine Universitas Indonesia-RSCM Kirana.

 2. Complete ophthalmological examination using a slit lamp will be conducted by the
 residence of Division of Neuro-ophthalmology.

 3. Examination of eye pressure using a non-contact tonometry (NCT).

 4. Fundus examination by fundus photograph operator.

 3. Patients who met the inclusion criteria for the study offered to follow this study.
 Researchers explain the purpose and procedures of the study, how the use of a given
 drug, and possible side effects of the drugs given. Patients who are willing to follow
 the study were asked to sign an informed consent.

 4. Subjects will be randomized into groups A (citicoline) or group B (placebo).

 5. Examination of the visual field using Humphrey HFA II-i 750, 24-2 threshold by anterior
 operator who has been certified.

 6. Examination of retinal ganglion cell thickness using OCT Cirrus TM (Trade Mark) by
 posterior operator who has been certified.

 7. Examination of pattern ERG by investigators, accompanied by an expert consultant in the
 Eye Clinic Division of Neuro-ophthalmology follow the standards of the International
 Society for Clinical electrophysiology of Vision (ISCEV)

 1. Before the examination, the eye drops of local anesthetic eye drops (pantocaine®)
 and eyelid and forehead area will be cleaned by abrasive paste and given a
 conductive paste.

 2. Fiber electrodes placed on the top edge of the eyelid inferior border of the nasal
 canthus area, reference electrodes on the skin area in the ipsilateral lateral
 canthus eyelids and grounding electrodes on the forehead.

 3. Standard stimulus parameter is set to be the size of a box of 0.80, luminance of 80
 cd / m2, contrast 100% reversal rate of 4 rev / s.

 4. Patients were asked to put the head on the head rest and a fixation on the letter X
 in the middle of the screen and it is recommended not much flash.

 5. Examination started and completed within 3-4 minutes to obtain a minimum of 100
 free wave artifacts.

 6. After completion of the examination, the patient's eye drops of antibiotic eye
 drops (C. Polygran®).

 8. Intervention: Subjects in group A get citicoline 1000 mg per day for 60 days while
 subjects in group B get placebo for 60 days (the citicoline and placebo will be
 repackage by the pharmacist).

 9. During the study, subjects continue taking systemic drug such as anti-hypertensive,
 anti-dyslipidemia, anti-diabetes, anti-coagulants as usual (control of risk factors) and
 not taking any other multivitamins.

 10. To ensure that patients taking the drug regularly study, the researchers will provide
 medication logbook and asking the patient to provide a check mark after taking the drug
 every day. Patients were asked to consume the drug in the morning after breakfast and a
 minimum of 60 minutes of consumption of other drugs (if any). Researchers also will call
 patients once a week to ensure that patients taking the study drug on a regular basis.

 11. Patients will be required to control after 30 days of drug usage for examination visual
 acuity, complete ophthalmologic examination, with Humphrey visual field examination,
 PERG examination and thickness of retinal ganglion cells by SD-OCT. Evaluation of
 logbook and noted complaints related to the side effects due to the intervention will
 also be assessed during follow up.

 12. After 60 days of intervention, re-examination include: visual acuity, complete
 ophthalmologic examination, Humphrey visual field examination, PERG examination and
 thickness of retinal ganglion cells using SD-OCT and also noted complaints related to
 side effects as a result of the intervention will be assessed during final follow up.

 13. The interpretation of the results of PERG performed by two expert consultants
 Neuro-Ophthalmology Division (MS and SN).

 Reporting Drug's Side Effects From previous studies, no serious side effects have been
 reported due to the use of this drug. In case of unwanted side effects such as headaches and
 gastrointestinal intolerance, researchers will ask the patient to come to the clinic Faculty
 of medicine Universitas Indonesia-RSCM Kirana and will be given further handling according
 the patient's condition and the researcher will decide whether the patient is still able to
 continue his research. The cost of treatment side effects will be borne by the researcher.
 Researchers also will ask the patient fill out a form and side effects of drugs.

 Operational definition

 1. Diagnosis of NAION established based on the following criteria: sudden decrease in
 visual acuity, optic disc edema or atrophy of optic nerve head on funduscopy, found
 relative afferent pupillary defect (if unilateral), visual field abnormalities (LP) is
 consistent with NAION. The diagnosis of NAION have been confirmed by the ophtalomologist
 in charge in Neuro-ophthalmology Policlinic Faculty of medicine Universitas
 Indonesia-RSCM Kirana. The acute phase is onset <6 weeks and found to have edema of
 optic nerve head in fundoscopy and or thickening of the Retinal Nerve Fiber Layer (RNFL)
 on the basis of at least one quadrant of optic nerve head OCT. Chronic phase is ≥ 6
 weeks from onset and found atrophy or normal of optic nerve head in funduscopy and RNFL
 thinning on the basis of at least one quadrant of optic nerve head OCT.

 2. Age: calculated based on years of research and a reduction in birth year of research
 subjects.

 3. Onset: calculated based on the first time the patient signed a consent form to
 participate study time minus the typical complaints NAION started happening.

 4. Best corrected visual acuity: the results of visual acuity using the Snellen maximum
 refraction correction chart. Visual acuity with correction is then converted to logMar

 5. Diabetes Mellitus (DM): The laboratory results of blood fasting blood sugar ≥ 126 mg /
 dL or random blood glucose and 2-hour post-prandial ≥ 200 mg / dL with classical symptom
 and or HbA1c ≥ 6.5% and or controlled DM with hypoglycemic drugs.

 6. Hypertension: Results of measurement of blood pressure ≥ 140/90 mmHg and or people with
 hypertension controlled with antihypertensive medication.

 7. Dyslipidemia: Results of laboratory blood total cholesterol ≥ 200 mg / dL or LDL ≥ 100
 mg / dL and HDL ≤ 50 mg / dL or triglyceride levels ≥ 100 mg / dL or persons with
 dyslipidemia and controlled dyslipidemia drugs.

 8. Hypercoagulability: blood lab results Ivy bleeding time <6 minutes or prothrombin time>
 11.2 seconds and or the activated partial thromboplastin time> 47 seconds or fibrinogen
 levels> 384 mg / dL or quantitative D-dimer> 300 g / dL or 1 μM platelet aggregation>
 15% and 5 μM or platelet aggregation> 68% or 10 μM platelet aggregation> 84%.

 9. Visual field is a visual field test results using Humphrey HFA II-i 750, 24-2 threshold.
 Examination is repeated by taking into account the confidence index that meets the three
 criteria below:

 1. Fixation losses ≤ 20%

 2. False positive ≤ 15%

 3. False negative ≤ 20-30%

 The parameters assessed are:

 1. The mean deviation (MD): the result of the average sensitivity of the retina of
 patients compared with the normal population. This figure is obtained from the
 total deviation.

 2. Pattern standard deviation (PSD): the result of the average sensitivity of the
 retina of patients who have adapted and showed a localized area index. This figure
 is obtained from the pattern deviation.

 10. The thickness of the retinal ganglion cells are anatomical cross-sectional examination
 of retinal ganglion cells using optical coherence tomography (OCT) Cirrus TM HD (High
 Definition) -OCT 5000. The mode is panomap ganglion cell analysis: Macular Cube 512x128
 and 200x200 cube Optic disc. Examination is repeated with minimal attention to signal
 strength is ≥ 5.

 11. PERG examination:

 1. P50 wave amplitude is amplitude measured from the valley of N35 to the peak of P50.
 The unit used is μV.

 2. N95 wave amplitude is the amplitude measured from peak of P50 to valley of N95. The
 unit used is μV.

 3. P50 wave implicit time is the time measured from the light stimulus to the crest of
 a wave P50. The unit used is ms.

 4. N95 wave implicit time is the time measured from the light stimulus to the crest of
 a wave N95. The unit used is ms.

 5. Latency is the time until the occurrence of a wave response.

 12. Side effects: systemic and ocular complaints at least 2 hours after study drug
 consumption. Side effects that have been reported previously were headache and
 gastrointestinal intolerance.

 Research Ethics Once the proposal is approved by research supervisor and research coordinator
 and Head of the Department of Ophthalmology Faculty of medicine Universitas Indonesia-RSCM
 Kirana, then the proposal will be submitted to the Health Research Ethics Committee of the
 Faculty of medicine Universitas Indonesia-RSCM for review. The study will begin after the
 study passed the test of ethics and obtained a number of research protocols to meet the
 Declaration of Helsinki and will be registered on the ClinicalTrials.gov website.

 Data analysis Data from the study will be recorded and incorporated into the primary table,
 then be processed with SPSS (Statistical Package for the Social Science) version 17.0. The
 analysis is intention to treat. If there is a violation of protocols such as the incidence of
 severe side-effects that provide interventions should be stopped or are lost to follow-up at
 least once a second measurement is done (after 30 days), the subject will be considered a
 failure but still included in the analysis. Patients were also said to drop out when during
 the administration of the intervention patients had symptoms of NAION in the contralateral
 eye and require steroid therapy but still included in the analysis had been carried out when
 at least a second measurement is done (after 30 days). Data will be presented in the form of
 tables and graphs. Data will be tested whether the distribution is spread evenly with
 normality test. Data were analyzed to compare the two averages in pairs using unpaired t-test
 or Mann Whitney test. Categorical data are presented in the form of proportions. Statistical
 test for difference in proportions between the two independent groups using chi-square test.
 Statistical tests to determine the correlation using Pearson or Spearman test.
Inclusion Criteria:

 1. Patients aged 20-65 years.

 2. NAION patients who have been diagnosed clinically by a minimum of 1 consultant
 Division NO with onset ≥6 weeks.

 3. Best corrected visual acuity ≥ 1/60 Snellen

 4. Patients have to get an explanation about the purpose of the research and all the
 procedures that will be undertaken and willing to participate in the study by signing
 the informed consent.

 5. On bilateral NAION, examination of research done on one eye at a nearby onset of 6
 weeks

 Exclusion Criteria:

 1. Haziness of refractive media, such as corneal opacities and opacities in the lens of
 moderate to severe (color and turbidity of the lens, the cortex and the posterior
 capsule with degrees LOCs III> 3).

 2. Abnormalities in the macula and the optic disc due to causes other than NAION.

 3. Patients with a history of glaucoma.

 4. Patients with intraocular inflammation such as anterior and posterior uveitis.

 5. Taking antioxidant supplements or other neuroprotective agents in the last 2 weeks
 before randomization.

 6. Edema of optic nerve head condition detected clinically or by OCT.