Official Title

Steroids for Corneal Ulcers Trial
  • Phase

    Phase 4
  • Study Type

    Interventional
  • Study Participants

    500
The purpose of this study is to determine whether adding topical steroids improves the outcomes of bacterial corneal ulcers, especially visual acuity.
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.
Study Started
Sep 30
2006
Primary Completion
Feb 28
2011
Study Completion
Dec 31
2012
Results Posted
Jun 14
2013
Estimate
Last Update
Aug 01
2018

Drug Antibiotics

moxifloxacin 0.5% every one hour for 48 hours while awake and then every 2 hours until re-epithelialization

  • Other names: Vigamox

Drug Topical corticosteroid

prednisolone phosphate 1% with preservative four times a day for 1 week, then twice a day for 1 week, and finally once a day for 1 week

Drug Placebo

0.9% NaCl and preservative (same as in steroid) four times a day for 1 week, then twice a day for 1 week, and finally once a day for 1 week

1 Active Comparator

2 Placebo Comparator

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

Summary

Steroid

Placebo

All Events

Event Type Organ System Event Term Steroid Placebo

Best Spectacle-corrected Visual Acuity (BSCVA) in logMAR at 3 Months, Using Best Spectacle-corrected Enrollment Visual Acuity as a Co-variate

LogMAR (logarithm of the Minimum Angle of Resolution) is a measure of visual acuity in which the smaller values indicate better visual acuity.

Steroid

0.48
logMAR (Mean)
95% Confidence Interval: 0.42 to 0.53

Placebo

0.49
logMAR (Mean)
95% Confidence Interval: 0.43 to 0.54

Ocular Perforations

Steroid

7.0
participants

Placebo

8.0
participants

Infiltrate/Scar Size, Correcting for Infiltrate/Scar Size at Enrollment

Placebo

3.02
mm (Mean)
95% Confidence Interval: 2.93 to 3.11

Steroid

3.07
mm (Mean)
95% Confidence Interval: 2.99 to 3.16

Best Hard Contact Lens Corrected Visual Acuity Measured in logMAR, Correcting for Best Spectacle Corrected Visual Acuity at Enrollment

LogMAR (logarithm of the Minimum Angle of Resolution) is a measure of visual acuity in which the smaller values indicate better visual acuity.

Steroid

0.42
logMAR (Mean)
95% Confidence Interval: 0.36 to 0.47

Placebo

0.41
logMAR (Mean)
95% Confidence Interval: 0.36 to 0.46

Best Spectacle-corrected Visual Acuity (BSCVA) in logMAR at 12 Months, Using Best Spectacle-corrected Enrollment Visual Acuity as a Co-variate

LogMAR (logarithm of the Minimum Angle of Resolution) is a measure of visual acuity in which the smaller values indicate better visual acuity.

Steroid

2.9
logMAR (Mean)
95% Confidence Interval: 2.8 to 3.01

Placebo

2.87
logMAR (Mean)
95% Confidence Interval: 2.77 to 2.98

Best Spectacle-corrected Visual Acuity (BSCVA) in logMAR Using MIC (Minimum Inhibitory Concentration) to Moxifloxacin as a Covariate

Best spectacle-corrected visual acuity (BSCVA) for this outcome is measured in logMAR (logarithm of the Minimum Angle of Resolution) in which smaller values indicate better visual acuity. Minimum inhibitory concentration (MIC) to moxifloxacin was measured by E test and a log2-transformation of MIC was used in all analyses. In this analysis we add MIC to the model examining BSCVA at 3 months.

Steroid

0.5
logMAR (Mean)
95% Confidence Interval: 0.58

Placebo

0.46
logMAR (Mean)
95% Confidence Interval: 0.49

Subgroup Analysis Predicting 3 Month Best Spectacle-corrected Visual Acuity (BSCVA) by Causative Organism

BSCVA measured in logMAR will be estimated by causative organism (either Nocardia spp, Streptococcus pneumoniae, Moraxella spp, or Pseudomonas aeruginosa). BSCVA will be examined for each causative organism by mean and standard deviation as well as in a regression model.

Steroid

Moraxella spp

0.46
logMAR (Mean)
Standard Deviation: 0.61

Nocardia spp

0.54
logMAR (Mean)
Standard Deviation: 0.67

Pseudomonas aeruginosa

0.53
logMAR (Mean)
Standard Deviation: 0.54

Streptococcus pneumoniae

0.49
logMAR (Mean)
Standard Deviation: 0.56

Placebo

Moraxella spp

0.26
logMAR (Mean)
Standard Deviation: 0.65

Nocardia spp

0.36
logMAR (Mean)
Standard Deviation: 0.64

Pseudomonas aeruginosa

0.45
logMAR (Mean)
Standard Deviation: 0.56

Streptococcus pneumoniae

0.52
logMAR (Mean)
Standard Deviation: 0.53

Subgroup Analysis Predicting 3 Month Best Spectacle-corrected Visual Acuity (BSCVA) by Visual Acuity Group

Best spectacle-corrected visual acuity (BSCVA) for this subgroup analysis was measured in logMAR and then categorized by equivalent Snellen fractions

Steroid

<20/40

0.06
logMAR (Mean)
Standard Deviation: 0.30

20/40 to 20/800

0.36
logMAR (Mean)
Standard Deviation: 0.43

Counting fingers (CF) or worse

1.0
logMAR (Mean)
Standard Deviation: 0.55

Placebo

<20/40

-0.02
logMAR (Mean)
Standard Deviation: 0.12

20/40 to 20/800

0.38
logMAR (Mean)
Standard Deviation: 0.38

Counting fingers (CF) or worse

1.15
logMAR (Mean)
Standard Deviation: 0.61

Subgroup Analysis of Best Spectacle-corrected Visual Acuity (BSCVA) by Categories of Infiltrate Depth

BSCVA measured in logMAR will be examined by categories infiltrate depth (categorized by depth percentage) by mean and standard deviation as well as in a regression model.

Steroid

>0-33%

0.35
logMAR (Mean)
Standard Deviation: 0.50

>33%-67%

0.52
logMAR (Mean)
Standard Deviation: 0.57

>67%-100%

0.8
logMAR (Mean)
Standard Deviation: 0.61

Placebo

>0-33%

0.26
logMAR (Mean)
Standard Deviation: 0.40

>33%-67%

0.47
logMAR (Mean)
Standard Deviation: 0.54

>67%-100%

0.86
logMAR (Mean)
Standard Deviation: 0.67

Time to Resolution of Epithelial Defect

This outcome measured time from enrollment to resolution of the epithelial defect in days for up to 21 days. For three weeks patients were examined every 3 days for size of epithelial defect until the defect was gone.

Steroid

9.77
days (Mean)
Standard Deviation: 7.54

Placebo

9.43
days (Mean)
Standard Deviation: 7.10

Subgroup Analysis Predicting Best Spectacle-corrected Visual Acuity (BSCVA) as Stratified by Categories of Infiltrate/Scar Size

Best-spectacle visual acuity (BSCVA) at 3 months from enrollment is stratified by categories of infiltrate/scar size and examined by treatment arm

Steroid

0-1.90 mm

0.18
logMAR (Mean)
Standard Deviation: 0.37

1.91-2.70 mm

0.39
logMAR (Mean)
Standard Deviation: 0.51

2.71-4.06 mm

0.53
logMAR (Mean)
Standard Deviation: 0.60

4.07-8.90 mm

0.85
logMAR (Mean)
Standard Deviation: 0.57

Placebo

0-1.90 mm

0.19
logMAR (Mean)
Standard Deviation: 0.33

1.91-2.70 mm

0.29
logMAR (Mean)
Standard Deviation: 0.44

2.71-4.06 mm

0.53
logMAR (Mean)
Standard Deviation: 0.53

4.07-8.90 mm

0.96
logMAR (Mean)
Standard Deviation: 0.67

Total

500
Participants

Age, Continuous

53.0
years (Median)
Inter-Quartile Range: 40.0 to 61.0

Age, Categorical

Region of Enrollment

Sex: Female, Male

Overall Study

Steroid

Placebo

Drop/Withdrawal Reasons

Steroid

Placebo