Citicoline Effect on Non-arteritic Anterior Ischemic Optic Neuropathy (NAION)

NCT03046693 | Completed Phase 4 DMC

• 1 other identifier: 16-11-501
• Study Type: interventional
• Target: 38
• Locations: 1 country
• Sites: 1

Brief 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?

Conditions

Non-arteritic Anterior Ischemic Optic Neuropathy

Keywords

Non-arteritic anterior ischemic optic neuropathy; pattern electroretinography; citicoline; retinal ganglion cell; visual field

Outcome Measures

Primary Outcomes (2)

• P50 wave amplitude

  amplitude measured from the valley of N35 to the peak of P50 with pattern electroretinography

  60 days

• N95 wave amplitude

  amplitude measured from peak of P50 to valley of N95 with pattern electroretinography

  60 days

Secondary Outcomes (2)

• thickness of the retinal ganglion cells

  60 days

• Visual field defect

  60 days

Study Arms (2)

Group A

EXPERIMENTAL

Subjects in group A get citicoline 1000 mg per day for 60 days

Drug: Group A Citicoline 1000 mg oral tablet

Group B

PLACEBO COMPARATOR

Subjects in group B get placebo for 60 days.

Drug: Group B placebo oral tablet

Interventions

Group A Citicoline 1000 mg oral tablet DRUG

Citicoline 1000 mg will be repackaged and given to Group A for 60 days

Group A

Group B placebo oral tablet DRUG

Placebo will be repackaged and given to Group B for 60 days

Group B

Eligibility Criteria

• Age: 20 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Patients aged 20-65 years.
• NAION patients who have been diagnosed clinically by a minimum of 1 consultant Division NO with onset ≥6 weeks.
• Best corrected visual acuity ≥ 1/60 Snellen
• 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.
• On bilateral NAION, examination of research done on one eye at a nearby onset of 6 weeks

You may not qualify if:

• 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).
• Abnormalities in the macula and the optic disc due to causes other than NAION.
• Patients with a history of glaucoma.
• Patients with intraocular inflammation such as anterior and posterior uveitis.
• Taking antioxidant supplements or other neuroprotective agents in the last 2 weeks before randomization.
• Edema of optic nerve head condition detected clinically or by OCT.

Sponsors & Collaborators

• Valen Chia: lead

Study Sites (1)

Departemen Mata Fakultas Kedokteran Universitas Indonesia- RSCM Kirana

Jakarta, DKI Jakarta, 10320, Indonesia

Location

Related Publications (17)

• Hayreh SS. Non-arteritic anterior ischemic optic neuropathy: role of systemic corticosteroid therapy. Surv Ophthalmol. 2010 Jul-Aug;55(4):399-400; author reply 400-1. doi: 10.1016/j.survophthal.2010.03.003. No abstract available.

  PMID: 20682167 RESULT

• Hayreh SS, Zimmerman MB. Nonarteritic anterior ischemic optic neuropathy: natural history of visual outcome. Ophthalmology. 2008 Feb;115(2):298-305.e2. doi: 10.1016/j.ophtha.2007.05.027. Epub 2007 Aug 15.

  PMID: 17698200 RESULT

• Grieb P. Neuroprotective properties of citicoline: facts, doubts and unresolved issues. CNS Drugs. 2014 Mar;28(3):185-93. doi: 10.1007/s40263-014-0144-8.

  PMID: 24504829 RESULT

• Secades JJ. Citicoline: pharmacological and clinical review, 2010 update. Rev Neurol. 2011 Mar 14;52 Suppl 2:S1-S62. English, Spanish.

  PMID: 21432836 RESULT

• Oshitari T, Fujimoto N, Adachi-Usami E. Citicoline has a protective effect on damaged retinal ganglion cells in mouse culture retina. Neuroreport. 2002 Nov 15;13(16):2109-11. doi: 10.1097/00001756-200211150-00023.

  PMID: 12438935 RESULT

• Parisi V, Coppola G, Ziccardi L, Gallinaro G, Falsini B. Cytidine-5'-diphosphocholine (Citicoline): a pilot study in patients with non-arteritic ischaemic optic neuropathy. Eur J Neurol. 2008 May;15(5):465-74. doi: 10.1111/j.1468-1331.2008.02099.x. Epub 2008 Mar 5.

  PMID: 18325025 RESULT

• Serra I, Alberghina M, Viola M, Mistretta A, Giuffrida AM. Effect of CDP-choline on the biosynthesis of nucleic acids and proteins in brain regions during hypoxia. Neurochem Res. 1981 Jun;6(6):607-18. doi: 10.1007/BF00963878.

  PMID: 6168928 RESULT

• Rejdak R, Toczolowski J, Solski J, Duma D, Grieb P. Citicoline treatment increases retinal dopamine content in rabbits. Ophthalmic Res. 2002 May-Jun;34(3):146-9. doi: 10.1159/000063658.

  PMID: 12097797 RESULT

• Levin LA. Axonal loss and neuroprotection in optic neuropathies. Can J Ophthalmol. 2007 Jun;42(3):403-8.

  PMID: 17508035 RESULT

• Galletti P, De Rosa M, Cotticelli MG, Morana A, Vaccaro R, Zappia V. Biochemical rationale for the use of CDPcholine in traumatic brain injury: pharmacokinetics of the orally administered drug. J Neurol Sci. 1991 Jul;103 Suppl:S19-25. doi: 10.1016/0022-510x(91)90004-q.

  PMID: 1940961 RESULT

• Weiss GB. Metabolism and actions of CDP-choline as an endogenous compound and administered exogenously as citicoline. Life Sci. 1995;56(9):637-60. doi: 10.1016/0024-3205(94)00427-t.

  PMID: 7869846 RESULT

• Grieb P, Rejdak R. Pharmacodynamics of citicoline relevant to the treatment of glaucoma. J Neurosci Res. 2002 Jan 15;67(2):143-8. doi: 10.1002/jnr.10129.

  PMID: 11782957 RESULT

• Schuettauf F, Rejdak R, Thaler S, Bolz S, Lehaci C, Mankowska A, Zarnowski T, Junemann A, Zagorski Z, Zrenner E, Grieb P. Citicoline and lithium rescue retinal ganglion cells following partial optic nerve crush in the rat. Exp Eye Res. 2006 Nov;83(5):1128-34. doi: 10.1016/j.exer.2006.05.021. Epub 2006 Jul 28.

  PMID: 16876158 RESULT

• Park CH, Kim YS, Lee HK, Kim YH, Choi MY, Jung DE, Yoo JM, Kang SS, Choi WS, Cho GJ. Citicoline reduces upregulated clusterin following kainic acid injection in the rat retina. Curr Eye Res. 2007 Dec;32(12):1055-63. doi: 10.1080/02713680701758719.

  PMID: 18085470 RESULT

• Rejdak R, Toczolowski J, Kurkowski J, Kaminski ML, Rejdak K, Stelmasiak Z, Grieb P. Oral citicoline treatment improves visual pathway function in glaucoma. Med Sci Monit. 2003 Mar;9(3):PI24-8.

  PMID: 12640353 RESULT

• Parisi V, Coppola G, Centofanti M, Oddone F, Angrisani AM, Ziccardi L, Ricci B, Quaranta L, Manni G. Evidence of the neuroprotective role of citicoline in glaucoma patients. Prog Brain Res. 2008;173:541-54. doi: 10.1016/S0079-6123(08)01137-0.

  PMID: 18929133 RESULT

• Parisi V. Electrophysiological assessment of glaucomatous visual dysfunction during treatment with cytidine-5'-diphosphocholine (citicoline): a study of 8 years of follow-up. Doc Ophthalmol. 2005 Jan;110(1):91-102. doi: 10.1007/s10633-005-7348-7.

  PMID: 16249960 RESULT

MeSH Terms

Interventions

Tablets

Intervention Hierarchy (Ancestors)

Dosage Forms; Pharmaceutical Preparations

Study Officials

• Valen Chia, MD

  Indonesia University

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: 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 citcoline) or group B (placebo) in accordance with the results of randomization. Neither the participant, investigator nor the outcome assessor know whether the patient is classified into group A or B.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: dr. Valenchia

Model Details: 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.

Study Record Dates

• First Submitted: February 5, 2017
• First Posted: February 8, 2017
• Study Start: January 16, 2017
• Primary Completion: April 1, 2017
• Study Completion: May 1, 2017
• Last Updated: September 7, 2017

Record last verified: 2017-09

Data Sharing

• IPD Sharing: Will not share

Locations

ID (1)