A double masked randomised 4-week, placebo-controlled study in the USA, Thailand and Taiwan to compare the efficacy of oral valganciclovir and topical 2% ganciclovir in the treatment of cytomegalovirus anterior uveitis: study protocol

Jaskirat S Takhar, Ashlin S Joye, Thanapong Somkijrungroj, Wipada Laovirojjanakul, Chang-Ping Lin, Thomas M Lietman, Travis C Porco, Jeremy D Keenan, Elisabeth A Gebreegziabher, Gerami D Seitzman, Jennifer Rose-Nussbaumer, Thuy A Doan, Nisha R Acharya, John A Gonzales, Jaskirat S Takhar, Ashlin S Joye, Thanapong Somkijrungroj, Wipada Laovirojjanakul, Chang-Ping Lin, Thomas M Lietman, Travis C Porco, Jeremy D Keenan, Elisabeth A Gebreegziabher, Gerami D Seitzman, Jennifer Rose-Nussbaumer, Thuy A Doan, Nisha R Acharya, John A Gonzales

Abstract

Introduction: Cytomegalovirus (CMV) anterior uveitis is a recognised cause of anterior uveitis in immunocompetent patients and is preventable cause of vision loss. Ocular sequelae include corneal endothelial damage which can cause corneal oedema and failure, as well as glaucoma. Recurrences of inflammation are common and therefore patients are often exposed to long-term therapy. Oral therapy is available in the form of valganciclovir, although with the caveat of systemic side effects such as bone marrow suppression and renal failure necessitating regular interval laboratory monitoring. Recent reports have demonstrated that topical 2% ganciclovir solution may offer promising treatment outcomes in patients with CMV anterior uveitis with superior safety, cost-effectiveness and convenience profiles. An investigation into the relative equipoise of these therapies is warranted for these reasons.

Methods and analysis: The Systemic and Topical Control of Cytomegalovirus Anterior uveitis: Treatment Outcomes (STACCATO) trial is designed as a multicentre, block randomised by site, double-masked, placebo-controlled trial comparing the efficacy of oral valganciclovir, 2% topical ganciclovir and placebo in treating PCR-proven CMV anterior uveitis. Participant clinical evaluation will occur at three study time points by a masked study ophthalmologist over a 28-day period to assess resolution of ocular inflammation (secondary outcome). A control group will provide additional information about the possible impact that the infected host's immune response may play in controlling local viral replication. The primary analysis is an analysis of covariance (three arms) correcting for baseline to compare quantitative CMV viral load in the anterior chamber (AC) aqueous fluid before and 7 days after treatment.

Ethics and dissemination: The University of California San Francisco Committee on Human Research and the Khon Kaen University Institutional Review Board have given ethical approval. The results of this trial will be presented at local and international meetings and submitted for peer-reviewed journals for publication.

Trial registration number: NCT03576898.

Keywords: cytomegalovirus; randomized clinical trial; uveitis.

Conflict of interest statement

Competing interests: None declared.

© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

References

    1. Markomichelakis NN, Canakis C, Zafirakis P, et al. . Cytomegalovirus as a cause of anterior uveitis with sectoral iris atrophy. Ophthalmology 2002;109:879–82. 10.1016/S0161-6420(02)00961-2
    1. Hwang Y-S, Shen C-R, Chang SHL, et al. . The validity of clinical feature profiles for cytomegaloviral anterior segment infection. Graefes Arch Clin Exp Ophthalmol 2011;249:103–10. 10.1007/s00417-010-1510-y
    1. Chee S-P, Jap A. Presumed Fuchs heterochromic iridocyclitis and Posner-Schlossman syndrome: comparison of cytomegalovirus-positive and negative eyes. Am J Ophthalmol 2008;146:883–9. 10.1016/j.ajo.2008.09.001
    1. Oral acyclovir for herpes simplex virus eye disease: effect on prevention of epithelial keratitis and stromal keratitis. herpetic eye disease Study Group. Arch Ophthalmol 2000;118:1030–6.
    1. McCann JD, Margolis TP, Wong MG, et al. . A sensitive and specific polymerase chain reaction-based assay for the diagnosis of cytomegalovirus retinitis. Am J Ophthalmol 1995;120:219–26. 10.1016/S0002-9394(14)72610-8
    1. Chee S-P, Bacsal K, Jap A, et al. . Clinical features of cytomegalovirus anterior uveitis in immunocompetent patients. Am J Ophthalmol 2008;145:834–40. 10.1016/j.ajo.2007.12.015
    1. Chee S-P, Bacsal K, Jap A, et al. . Corneal endotheliitis associated with evidence of cytomegalovirus infection. Ophthalmology 2007;114:798–803. 10.1016/j.ophtha.2006.07.057
    1. Alfawaz A. Cytomegalovirus-Related corneal endotheliitis: a review article. Saudi J Ophthalmol 2013;27:47–9. 10.1016/j.sjopt.2011.10.001
    1. Koizumi N, Suzuki T, Uno T, et al. . Cytomegalovirus as an etiologic factor in corneal endotheliitis. Ophthalmology 2008;115:292–7. 10.1016/j.ophtha.2007.04.053
    1. Ang M, Sng CCA, Chee S-P, et al. . Outcomes of corneal transplantation for irreversible corneal decompensation secondary to corneal endotheliitis in Asian eyes. Am J Ophthalmol 2013;156:260–6. 10.1016/j.ajo.2013.03.020
    1. Sonoyama H, Araki-Sasaki K, Osakabe Y, et al. . Detection of cytomegalovirus DNA from cytomegalovirus corneal endotheliitis after penetrating keratoplasty. Cornea 2010;29:683–5. 10.1097/ICO.0b013e3181c325e2
    1. Anshu A, Chee S-P, Mehta JS, et al. . Cytomegalovirus endotheliitis in Descemet's stripping endothelial keratoplasty. Ophthalmology 2009;116:624–30. 10.1016/j.ophtha.2008.10.031
    1. Abou Shousha M, Yoo SH, Sayed MS, et al. . In Vivo Characteristics of Corneal Endothelium/Descemet Membrane Complex for the Diagnosis of Corneal Graft Rejection. Am J Ophthalmol 2017;178:27–37. 10.1016/j.ajo.2017.02.026
    1. Basilious A, Chew HF. Topical ganciclovir for prophylaxis of cytomegalovirus Endotheliitis in endothelial keratoplasty. Cornea 2019;38:120–2. 10.1097/ICO.0000000000001797
    1. Accorinti M, Gilardi M, Pirraglia MP, et al. . Cytomegalovirus anterior uveitis: long-term follow-up of immunocompetent patients. Graefes Arch Clin Exp Ophthalmol 2014;252:1817–24. 10.1007/s00417-014-2782-4
    1. Choi JA, Kim J-E, Noh S-J, et al. . Enhanced cytomegalovirus infection in human trabecular meshwork cells and its implication in glaucoma pathogenesis. Sci Rep 2017;7:43349 10.1038/srep43349
    1. Xi L, Zhang L, Fei W. Cytomegalovirus-Related uncontrolled glaucoma in an immunocompetent patient: a case report and systematic review. BMC Ophthalmol 2018;18:259 10.1186/s12886-018-0917-9
    1. Zandi S, Bodaghi B, Garweg JG. Review for disease of the year: treatment of viral anterior uveitis: a perspective. Ocul Immunol Inflamm 2018;26:1135–42. 10.1080/09273948.2018.1498109
    1. Pleyer U, Chee S-P. Current aspects on the management of viral uveitis in immunocompetent individuals. OPTH 2015;9:1017–28. 10.2147/OPTH.S60394
    1. CC S, FR H, Wang TH, et al. . Clinical outcomes in cytomegalovirus-positive Posner-Schlossman syndrome patients treated with topical ganciclovir therapy. Am J Ophthalmol 2014;158:1024–31.
    1. Wong JXH, Agrawal R, Wong EPY, et al. . Efficacy and safety of topical ganciclovir in the management of cytomegalovirus (CMV)-related anterior uveitis. J Ophthalmic Inflamm Infect 2016;6:10 10.1186/s12348-016-0078-z
    1. CC S, Wang IJ, Chen WL, et al. . Topical ganciclovir treatment in patients with cytomegalovirus endotheliitis receiving penetrating keratoplasty. Clin Exp Ophthalmol 2013;41:339–47.
    1. Keorochana N, Choontanom R. Efficacy and safety of an extemporaneous preparation of 2% ganciclovir eye drops in CMV anterior uveitis. BMJ Open Ophth 2017;2:e000061 10.1136/bmjophth-2016-000061
    1. Antoun J, Willermain F, Makhoul D, et al. . Topical ganciclovir in cytomegalovirus anterior uveitis. J Ocul Pharmacol Ther 2017;33:313–8. 10.1089/jop.2016.0138
    1. A CS J. Cytomegalovirus-Associated anterior segment inflammation. Expert Review of Ophthalmology 2011;5:517–28.
    1. Chan A-W TJ, Altman DG, Laupacis A, et al. . Statement: defining standard protocol items for clinical trials. Ann Intern Med 2013;2013:200–7.
    1. Wong A, Tan KH, Tee CS, et al. . Seroprevalence of cytomegalovirus, Toxoplasma and parvovirus in pregnancy. Singapore Med J 2000;41:151–5.
    1. Taechowisan T, Sutthent R, Louisirirotchanakul S, et al. . Immune status in congenital infections by torch agents in pregnant Thais. Asian Pac J Allergy Immunol 1997;15:93–7.
    1. Tookey PA, Ades AE, Peckham CS. Cytomegalovirus prevalence in pregnant women: the influence of parity. Arch Dis Child 1992;67:779–83. 10.1136/adc.67.7_Spec_No.779
    1. Trivedi D, Denniston AKO, Murray PI. Safety profile of anterior chamber paracentesis performed at the slit lamp. Clin Exp Ophthalmol 2011;39:725–8. 10.1111/j.1442-9071.2011.02565.x
    1. Roche Pharmaceuticals Valganciclovir package insert. Available:
    1. Kandori M, Inoue T, Takamatsu F, et al. . Prevalence and features of keratitis with quantitative polymerase chain reaction positive for cytomegalovirus. Ophthalmology 2010;117:216–22. 10.1016/j.ophtha.2009.06.059
    1. Kawaguchi T, Sugita S, Shimizu N, et al. . Kinetics of aqueous flare, intraocular pressure and virus-DNA copies in a patient with cytomegalovirus iridocyclitis without retinitis. Int Ophthalmol 2007;27:383–6. 10.1007/s10792-007-9090-5
    1. Kandori M, Miyazaki D, Yakura K, et al. . Relationship between the number of cytomegalovirus in anterior chamber and severity of anterior segment inflammation. Jpn J Ophthalmol 2013;57:497–502. 10.1007/s10384-013-0268-2

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