To compare the efficacy and safety of HU00701 (0.01% cyclosporin A + 3% trehalose), HU007 (0.02% cyclosporin A + 3% trehalose) (all w/v), and placebo in patients with moderate to severe dry eye disease (DED).
Methods:
This was a multicenter, randomized, double-masked, parallel, placebo-controlled phase II study. In total, 114 patients were randomly assigned to the HU00701, HU007, placebo, or reference group. There was a 2-week run-in period before the 12-week intervention. Efficacy and safety were evaluated every 4 weeks.
Results:
The primary endpoint, change in corneal staining score from baseline to week 12, did not differ significantly among the control, HU00701, and HU007 groups in the full analysis. Of the secondary endpoints, only the tear film breakup time differed significantly at week 12 between the placebo and HU00701 groups. Twenty adverse events were reported by 15 patients, but the rate did not differ significantly among the 4 groups. The laboratory test, vital signs, and physical examination data showed no significant changes during the study.
Conclusions:
HU00701 and HU007 are safe, and HU007 effectively reduces the corneal staining score in patients with moderate-to-severe DED (NCT02917512).
MossS.E., KleinR., and KleinB.E.Prevalence of and risk factors for dry eye syndrome. Arch. Ophthalmol. 118:1264–1268, 2000.
4.
CraigJ.P., NicholsK.K., AkpekE.K., CafferyB., DuaH.S., JooC.K., LiuZ., NelsonJ.D., NicholsJ.J., TsubotaK., and StapletonF.TFOS DEWS II definition and classification report. Ocul. Surf. 15:276–283, 2017.
5.
JonesL., DownieL.E., KorbD., Benitez-Del-CastilloJ.M., DanaR., DengS.X., DongP.N., GeerlingG., HidaR.Y., LiuY., SeoK.Y., TauberJ., WakamatsuT.H., XuJ., WolffsohnJ.S., and CraigJ.P.TFOS DEWS II management and therapy report. Ocul. Surf. 15:575–628, 2017.
6.
MarshP., and PflugfelderS.C.Topical nonpreserved methylprednisolone therapy for keratoconjunctivitis sicca in Sjogren syndrome. Ophthalmology. 106:811–816, 1999.
7.
DonnenfeldE., and PflugfelderS.C.Topical ophthalmic cyclosporine: pharmacology and clinical uses. Surv. Ophthalmol. 54:321–338, 2009.
8.
MatsudaS., and KoyasuS.Mechanisms of action of cyclosporine. Immunopharmacology. 47:119–125, 2000.
9.
KunertK.S., TisdaleA.S., SternM.E., SmithJ.A., and GipsonI.K.Analysis of topical cyclosporine treatment of patients with dry eye syndrome: effect on conjunctival lymphocytes. Arch. Ophthalmol. 118:1489–1496, 2000.
10.
BrignoleF., PisellaP.J., De Saint JeanM., GoldschildM., GoguelA., and BaudouinC.Flow cytometric analysis of inflammatory markers in KCS: 6-month treatment with topical cyclosporin A. Invest. Ophthalmol. Vis. Sci. 42:90–95, 2001.
11.
de OliveiraR.C., and WilsonS.E.Practical guidance for the use of cyclosporine ophthalmic solutions in the management of dry eye disease. Clin. Ophthalmol. 13:1115–1122, 2019.
12.
Tang-LiuD.D., and AcheampongA.Ocular pharmacokinetics and safety of ciclosporin, a novel topical treatment for dry eye. Clin. Pharmacokinet. 44:247–261, 2005.
13.
LuyckxJ., and BaudouinC.Trehalose: an intriguing disaccharide with potential for medical application in ophthalmology. Clin. Ophthalmol. 5:577–581, 2011.
14.
JainN.K., and RoyI.Trehalose and protein stability. Curr. Protoc. Protein Sci. Chapter 4:Unit 4 9, 2010; DOI: 10.1002/0471140864.ps0409s59.
15.
BenaroudjN., LeeD.H., and GoldbergA.L.Trehalose accumulation during cellular stress protects cells and cellular proteins from damage by oxygen radicals. J. Biol. Chem. 276:24261–24267, 2001.
16.
BronA.J., EvansV.E., and SmithJ.A.Grading of corneal and conjunctival staining in the context of other dry eye tests. Cornea. 22:640–650, 2003.
17.
IbrahimO.M., DogruM., WardS.K., MatsumotoY., WakamatsuT.H., IshidaK., TsuyamaA., KojimaT., ShimazakiJ., and TsubotaK.The efficacy, sensitivity, and specificity of strip meniscometry in conjunction with tear function tests in the assessment of tear meniscus. Invest. Ophthalmol Vis. Sci. 52:2194–2198, 2011.
18.
MengherL.S., BronA.J., TongeS.R., and GilbertD.J.A non-invasive instrument for clinical assessment of the pre-corneal tear film stability. Curr. Eye. Res. 4:1–7, 1985.
19.
KorbD.R., HermanJ.P., GreinerJ.V., ScaffidiR.C., FinnemoreV.M., ExfordJ.M., BlackieC.A., and DouglassT.Lid wiper epitheliopathy and dry eye symptoms. Eye Contact Lens. 31:2–8, 2005.
20.
KorbD.R., ScaffidiR.C., GreinerJ.V., KenyonK.R., HermanJ.P., BlackieC.A., GlonekT., CaseC.L., FinnemoreV.M., and DouglassT.The effect of two novel lubricant eye drops on tear film lipid layer thickness in subjects with dry eye symptoms. Optom. Vis. Sci. 82:594–601, 2005.
21.
AsieduK.Rasch analysis of the Standard Patient Evaluation of Eye Dryness questionnaire. Eye Contact Lens. 43:394–398, 2017.
22.
GoldbergD.F., MalhotraR.P., SchechterB.A., JusticeA., WeissS.L., and SheppardJ.D.A phase 3, randomized, double-masked study of OTX-101 ophthalmic solution 0.09% in the treatment of dry eye disease. Ophthalmology. 126:1230–1237, 2019.
23.
WirtaD.L., TorkildsenG.L., MoreiraH.R., LonsdaleJ.D., CiolinoJ.B., JentschG., BeckertM., OuslerG.W., StevenP., and KrösserS.A clinical phase II study to assess efficacy, safety, and tolerability of waterfree cyclosporine formulation for treatment of dry eye disease. Ophthalmology. 126:792–800, 2019.
24.
LeonardiA., DoanS., AmraneM., IsmailD., MonteroJ., NemethJ., AragonaP., Bremond-GignacD., and GroupV.S.A randomized, controlled trial of cyclosporine A cationic emulsion in pediatric vernal keratoconjunctivitis: the VEKTIS study. Ophthalmology. 126:671–681, 2019.
25.
KimC.Y., ParkK.H., AhnJ., AhnM.D., ChaS.C., KimH.S., KimJ.M., KimM.J., KimT.W., KimY.Y., LeeJ.W., ParkS.W., SohnY.H., SungK.R., YooC., ChaJ., and KimY.J.Treatment patterns and medication adherence of patients with glaucoma in South Korea. Br. J. Ophthalmol. 101:801–807, 2017.
26.
TsumuraT., KashiwagiK., SuzukiY., YoshikawaK., SuzumuraH., MaedaT., TakedaR., SaitoH., and AraieM.A nationwide survey of factors influencing adherence to ocular hypotensive eyedrops in Japan. Int. Ophthalmol. 39:375–383, 2019.
27.
Newman-CaseyP.A., RobinA.L., BlachleyT., FarrisK., HeislerM., ResnicowK., and LeeP.P.The most common barriers to glaucoma medication adherence: A cross-sectional survey. Ophthalmology. 122:1308–1316, 2015.
28.
WhiteD.E., ZhaoY., OgundeleA., FulcherN., AcsA., Moore-SchiltzL., and KarpeckiP.M.Real-world treatment patterns of cyclosporine ophthalmic emulsion and lifitegrast ophthalmic solution among patients with dry eye. Clin. Ophthalmol. 13:2285–2292, 2019.
29.
WanK.H., ChenL.J., and YoungA.L.Efficacy and safety of topical 0.05% cyclosporine eye drops in the treatment of dry eye syndrome: a systematic review and meta-analysis. Ocul. Surf. 13:213–225, 2015.
30.
SallK., StevensonO.D., MundorfT.K., and ReisB.L.Two multicenter, randomized studies of the efficacy and safety of cyclosporine ophthalmic emulsion in moderate to severe dry eye disease. CsA Phase 3 Study Group. Ophthalmology. 107:631–639, 2000.
31.
ChenQ., and HaddadG.G.Role of trehalose phosphate synthase and trehalose during hypoxia: from flies to mammals. J. Exp. Biol. 207:3125–3129, 2004.
32.
MatsuoT.Trehalose versus hyaluronan or cellulose in eyedrops for the treatment of dry eye. Jpn. J. Ophthalmol. 48:321–327, 2004.
33.
WozniakP.A., SchmidlD., BataA.M., FondiK., WitkowskaK.J., Aranha Dos SantosV., BaarC., RoomK.I., NeppJ., BaumgartnerI., Popa-CherecheanuA., GarhoferG., WerkmeisterR.M., and SchmettererL.Effect of different lubricant eye gels on tear film thickness as measured with ultrahigh-resolution optical coherence tomography. Acta Ophthalmol. 95:e307–e313, 2017.
34.
ChiambarettaF., DoanS., LabetoulleM., RocherN., FekihL.E., MessaoudR., KhairallahM., BaudouinC., and GroupHA-tS. A randomized, controlled study of the efficacy and safety of a new eyedrop formulation for moderate to severe dry eye syndrome. Eur. J. Ophthalmol. 27:1–9, 2017.
35.
Pinto-BonillaJ.C., Del Olmo-JimenoA., Llovet-OsunaF., and Hernandez-GalileaE.A randomized crossover study comparing trehalose/hyaluronate eyedrops and standard treatment: patient satisfaction in the treatment of dry eye syndrome. Ther. Clin. Risk. Manag. 11:595–603, 2015.
36.
StevensonD., TauberJ., and ReisB.L.Efficacy and safety of cyclosporin A ophthalmic emulsion in the treatment of moderate-to-severe dry eye disease: a dose-ranging, randomized trial. The Cyclosporin A Phase 2 Study Group. Ophthalmology. 107:967–974, 2000.
37.
StonecipherK.G., TorkildsenG.L., OuslerG.W., MorrisS., VillanuevaL., and HollanderD.A.The IMPACT study: a prospective evaluation of the effects of cyclosporine ophthalmic emulsion 0.05% on ocular surface staining and visual performance in patients with dry eye. Clin. Ophthalmol. 10:887–895, 2016.
Supplementary Material
Please find the following supplemental material available below.
For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.
For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.
