Citicoline Effect on Non-arteritic Anterior Ischemic Optic Neuropathy (NAION)
Condition: Non-arteritic Anterior Ischemic Optic Neuropathy
MeSH terms: Peripheral Nervous System Diseases; Optic Nerve Diseases; Optic Neuropathy, Ischemic; Ischemia
Study type: Interventional
Phase: Phase 4

Summary: 
      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?
    

Detailed description: 
      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.
    

Intervention name(s): Group A Citicoline 1000 mg oral tablet; Group B placebo oral tablet
Intervention type(s): Drug; Drug
Intervention description(s): Citicoline 1000 mg will be repackaged and given to Group A for 60 days; Placebo will be repackaged and given to Group B for 60 days
Intervention MeSH terms: Cytidine Diphosphate Choline
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: Sample of 20 people for each treatment group (Group A: citicoline and group B : placebo). Both group were given drug (whether citicoline or placebo) for 60 days.
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: Non-arteritic anterior ischemic optic neuropathy; pattern electroretinography; citicoline; retinal ganglion cell; visual field