Clinical trial NCT00324168: Steroids for Corneal Ulcers Trial
Official title: Steroids for Corneal Ulcers Trial
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Corneal Ulcer
Eye Infections, Bacterial
Keywords: Bacterial Infections
Eye Diseases
Bacterial Keratitis
Visual Acuity
Lead sponsor: University of California, San Francisco
Sponsor class: OTHER
Collaborators: name: Aravind Eye Hospitals, India
name: Dartmouth-Hitchcock Medical Center
name: National Eye Institute (NEI)
First posted: 2006-05-10
Enrollment: 500
Sex: ALL
Minimum age (years): 16
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The purpose of this study is to determine whether adding topical steroids improves the outcomes of bacterial corneal ulcers, especially visual acuity.

Detailed description: Antimicrobial treatment of a bacterial corneal ulcer is generally effective in eradicating infection. However, "successful" treatment is not always associated with a good visual outcome. The scarring that accompanies the resolution of infection leaves many eyes blind. Some cornea specialists advocate the use of topical corticosteroids along with antibiotics in an effort to reduce immune-mediated tissue damage and scarring. Others fear using steroids to reduce the cornea's immune response will prolong or even exacerbate infection. Ophthalmologists have been divided on this issue for more than 30 years, and both approaches are acceptable according to the American Academy of Ophthalmology's Preferred Practice Patterns. Evidence from animal and human reports is mixed. A single randomized trial saw a non-significant benefit to steroids but was drastically underpowered (20 patients per study arm).

The study is a randomized, double-masked, placebo-controlled trial to determine whether adding topical steroids improves the outcomes of bacterial corneal ulcers. Five hundred bacterial corneal ulcers presenting to the Aravind Eye Hospitals, the University of California, San Francisco (UCSF) Proctor Foundation, and the Dartmouth-Hitchcock Medical Center will be randomized to receive antibiotic plus steroid or antibiotic plus placebo. Participants will be followed closely until re-epithelialization and then rechecked at three weeks, three months and 12 months post enrollment. A subset of patients will be contacted for a follow-up visit four years post enrollment. The primary outcome is best spectacle-corrected visual acuity three months after enrollment, using best spectacle-corrected enrollment visual acuity as a co-variate.

A pilot study was conducted from January 2005 to August 2005 at Aravind Eye Hospital to assess the feasibility and safety and to estimate the sample size of a larger main trial. Forty-two patients with culture-proven bacterial keratitis were enrolled. They were treated and followed up as in the main trial, up to three months from enrollment.

Eligibility criteria: Inclusion Criteria

At Presentation:

* Presence of a corneal ulcer at presentation

At Enrollment:

* Presence of bacteria on blood or chocolate agar culture
* Antibiotic given for \> 48 hours
* The patient must be able to verbalize a basic understanding of the study after it is explained to the patient, as determined by physician examiner. This understanding must include a commitment to return for f/u visits.
* Appropriate consent

Exclusion Criteria

At Presentation:

* Overlying epithelial defect \< 0.75 mm at its greatest width at presentation
* Corneal perforation or impending perforation
* Evidence of fungus on KOH, Giemsa at time of presentation
* Evidence of acanthamoeba by stain
* Evidence of herpetic keratitis by history or exam
* Corneal scar not easily distinguishable from current ulcer
* Use of a topical steroid in the affected eye during the course of the present ulcer, including use after the symptoms of the ulcer started but before presentation
* Use of systemic prednisolone during the course of the present ulcer
* Age less than 16 years (before 16th birthday)
* Bilateral ulcers
* Previous penetrating keratoplasty
* Pregnancy (by history or urine test)
* Immediate steroid use necessary due to surgery or other condition

At Enrollment:

* Evidence of fungus on culture at time of enrollment
* Absence of bacteria on blood or chocolate agar culture
* Best spectacle-corrected vision worse than 6/60 in the fellow eye
* Corneal perforation or descemetocele
* Known allergy to study medications (steroid or preservative)
* No light perception in the affected eye
* Not willing to come to follow-up visits
* Not willing to participate

Primary outcomes:
measure: Best Spectacle-corrected Visual Acuity (BSCVA) in logMAR at 3 Months, Using Best Spectacle-corrected Enrollment Visual Acuity as a Co-variate
timeFrame: 3 months from enrollment
Secondary outcomes:
measure: Infiltrate/Scar Size, Correcting for Infiltrate/Scar Size at Enrollment
timeFrame: 3 months from enrollment
measure: Best Hard Contact Lens Corrected Visual Acuity Measured in logMAR, Correcting for Best Spectacle Corrected Visual Acuity at Enrollment
timeFrame: 3 months from enrollment
measure: Time to Resolution of Epithelial Defect
timeFrame: From enrollment up to 21 days
measure: Ocular Perforations
timeFrame: At the time of perforation
measure: Best Spectacle-corrected Visual Acuity (BSCVA) in logMAR at 12 Months, Using Best Spectacle-corrected Enrollment Visual Acuity as a Co-variate
timeFrame: 12 months from enrollment
measure: Best Spectacle-corrected Visual Acuity (BSCVA) in logMAR Using MIC (Minimum Inhibitory Concentration) to Moxifloxacin as a Covariate
timeFrame: 3 months after enrollment
measure: Subgroup Analysis Predicting 3 Month Best Spectacle-corrected Visual Acuity (BSCVA) by Causative Organism
timeFrame: 3 months after enrollment
measure: Subgroup Analysis Predicting 3 Month Best Spectacle-corrected Visual Acuity (BSCVA) by Visual Acuity Group
timeFrame: 3 months from enrollment
measure: Subgroup Analysis of Best Spectacle-corrected Visual Acuity (BSCVA) by Categories of Infiltrate Depth
timeFrame: 3 months from enrollment
measure: Subgroup Analysis Predicting Best Spectacle-corrected Visual Acuity (BSCVA) as Stratified by Categories of Infiltrate/Scar Size
timeFrame: 3 months from enrollment
Other outcomes:
Locations:
city: San Francisco
country: United States
facility: Proctor Foundation, UCSF
state: California
city: Lebanon
country: United States
facility: Dartmouth Hitchcock Medical Center
state: New Hampshire
city: Coimbatore
country: India
facility: Aravind Eye Hospital
state: Tamil Nadu
city: Madurai
country: India
facility: Aravind Eye Hospital
state: Tamil Nadu
city: Tirunelveli
country: India
facility: Aravind Eye Hospital
state: Tamil Nadu
Study officials:
affiliation: Aravind Eye Hospital
name: M. Srinivasan, M.S., O.D.
role: PRINCIPAL_INVESTIGATOR
affiliation: Dartmouth-Hitchcock Medical Center
name: Mike Zegans, M.D.
role: PRINCIPAL_INVESTIGATOR
affiliation: Proctor Foundation, UCSF
name: Nisha Acharya, M.D., M.S.
role: PRINCIPAL_INVESTIGATOR
affiliation: Proctor Foundation, UCSF
name: Thomas M Lietman, M.D.
role: STUDY_DIRECTOR
References:
citation: Srinivasan M, Mascarenhas J, Rajaraman R, Ravindran M, Lalitha P, Glidden DV, Ray KJ, Hong KC, Oldenburg CE, Lee SM, Zegans ME, McLeod SD, Lietman TM, Acharya NR; Steroids for Corneal Ulcers Trial Group. The steroids for corneal ulcers trial: study design and baseline characteristics. Arch Ophthalmol. 2012 Feb;130(2):151-7. doi: 10.1001/archophthalmol.2011.303. Epub 2011 Oct 10.
citation: Srinivasan M, Mascarenhas J, Rajaraman R, Ravindran M, Lalitha P, Glidden DV, Ray KJ, Hong KC, Oldenburg CE, Lee SM, Zegans ME, McLeod SD, Lietman TM, Acharya NR; Steroids for Corneal Ulcers Trial Group. Corticosteroids for bacterial keratitis: the Steroids for Corneal Ulcers Trial (SCUT). Arch Ophthalmol. 2012 Feb;130(2):143-50. doi: 10.1001/archophthalmol.2011.315. Epub 2011 Oct 10.
citation: Hammond JH, Hebert WP, Naimie A, Ray K, Van Gelder RD, DiGiandomenico A, Lalitha P, Srinivasan M, Acharya NR, Lietman T, Hogan DA, Zegans ME. Environmentally Endemic Pseudomonas aeruginosa Strains with Mutations in lasR Are Associated with Increased Disease Severity in Corneal Ulcers. mSphere. 2016 Sep 7;1(5):e00140-16. doi: 10.1128/mSphere.00140-16. eCollection 2016 Sep-Oct.
citation: McClintic SM, Prajna NV, Srinivasan M, Mascarenhas J, Lalitha P, Rajaraman R, Oldenburg CE, O'Brien KS, Ray KJ, Acharya NR, Lietman TM, Keenan JD. Visual outcomes in treated bacterial keratitis: four years of prospective follow-up. Invest Ophthalmol Vis Sci. 2014 May 2;55(5):2935-40. doi: 10.1167/iovs.14-13980.
citation: Srinivasan M, Mascarenhas J, Rajaraman R, Ravindran M, Lalitha P, Ray KJ, Zegans ME, Acharya NR, Lietman TM, Keenan JD; Steroids for Corneal Ulcers Trial Group. Visual recovery in treated bacterial keratitis. Ophthalmology. 2014 Jun;121(6):1310-1. doi: 10.1016/j.ophtha.2013.12.041. Epub 2014 Mar 5.
citation: Srinivasan M, Mascarenhas J, Rajaraman R, Ravindran M, Lalitha P, O'Brien KS, Glidden DV, Ray KJ, Oldenburg CE, Zegans ME, Whitcher JP, McLeod SD, Porco TC, Lietman TM, Acharya NR; Steroids for Corneal Ulcers Trial Group. The steroids for corneal ulcers trial (SCUT): secondary 12-month clinical outcomes of a randomized controlled trial. Am J Ophthalmol. 2014 Feb;157(2):327-333.e3. doi: 10.1016/j.ajo.2013.09.025. Epub 2013 Oct 1.
citation: Oldenburg CE, Lalitha P, Srinivasan M, Manikandan P, Bharathi MJ, Rajaraman R, Ravindran M, Mascarenhas J, Nardone N, Ray KJ, Glidden DV, Acharya NR, Lietman TM. Moxifloxacin susceptibility mediates the relationship between causative organism and clinical outcome in bacterial keratitis. Invest Ophthalmol Vis Sci. 2013 Feb 28;54(2):1522-6. doi: 10.1167/iovs.12-11246.
citation: Ray KJ, Prajna L, Srinivasan M, Geetha M, Karpagam R, Glidden D, Oldenburg CE, Sun CQ, McLeod SD, Acharya NR, Lietman TM. Fluoroquinolone treatment and susceptibility of isolates from bacterial keratitis. JAMA Ophthalmol. 2013 Mar;131(3):310-3. doi: 10.1001/jamaophthalmol.2013.1718.
citation: Lalitha P, Srinivasan M, Rajaraman R, Ravindran M, Mascarenhas J, Priya JL, Sy A, Oldenburg CE, Ray KJ, Zegans ME, McLeod SD, Lietman TM, Acharya NR. Nocardia keratitis: clinical course and effect of corticosteroids. Am J Ophthalmol. 2012 Dec;154(6):934-939.e1. doi: 10.1016/j.ajo.2012.06.001. Epub 2012 Sep 5.
citation: Lalitha P, Srinivasan M, Manikandan P, Bharathi MJ, Rajaraman R, Ravindran M, Cevallos V, Oldenburg CE, Ray KJ, Toutain-Kidd CM, Glidden DV, Zegans ME, McLeod SD, Acharya NR, Lietman TM. Relationship of in vitro susceptibility to moxifloxacin and in vivo clinical outcome in bacterial keratitis. Clin Infect Dis. 2012 May;54(10):1381-7. doi: 10.1093/cid/cis189. Epub 2012 Mar 23.
citation: Dalmon C, Porco TC, Lietman TM, Prajna NV, Prajna L, Das MR, Kumar JA, Mascarenhas J, Margolis TP, Whitcher JP, Jeng BH, Keenan JD, Chan MF, McLeod SD, Acharya NR. The clinical differentiation of bacterial and fungal keratitis: a photographic survey. Invest Ophthalmol Vis Sci. 2012 Apr 2;53(4):1787-91. doi: 10.1167/iovs.11-8478.
citation: Sy A, Srinivasan M, Mascarenhas J, Lalitha P, Rajaraman R, Ravindran M, Oldenburg CE, Ray KJ, Glidden D, Zegans ME, McLeod SD, Lietman TM, Acharya NR. Pseudomonas aeruginosa keratitis: outcomes and response to corticosteroid treatment. Invest Ophthalmol Vis Sci. 2012 Jan 25;53(1):267-72. doi: 10.1167/iovs.11-7840.
citation: Srinivasan M, Lalitha P, Mahalakshmi R, Prajna NV, Mascarenhas J, Chidambaram JD, Lee S, Hong KC, Zegans M, Glidden DV, McLeod S, Whitcher JP, Lietman TM, Acharya NR. Corticosteroids for bacterial corneal ulcers. Br J Ophthalmol. 2009 Feb;93(2):198-202. doi: 10.1136/bjo.2008.147298. Epub 2008 Oct 1.