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Speaker: Standardized definitions, endpoints should drive cross-linking trials
Inclusion criteria, definitions of progression and endpoints vary, resulting in a lack of standardized data.
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As clinical trials for corneal collagen cross-linking proceed, clinicians should use standardized definitions and metrics to evaluate the effectiveness of treatment, according to a speaker at the World Cornea Congress in San Diego.
“If we’re going to say that cross-linking prevents progression, we need to measure progression,” Penny A. Asbell, MD, FACS, MBA, OSN Contact Lenses Section Editor, told Ocular Surgery News in a subsequent interview. “The key issues for treatment of keratoconus are prevention of progression and improvement of best corrected spectacle vision. Those are the endpoints that we typically use to determine whether or not the treatment was helpful. Although I must say that for CXL, most researchers concentrate on preventing progression.”
Investigators have used a variety of criteria to define progression, such as keratometry, topography, vision, corneal thickness, need for contact lenses and need for surgery, Asbell said.
Natural history
“The natural history of progression of keratoconus is probably more complex than we thought; there are a lot of patients who, once they are diagnosed, seem pretty stable for years thereafter and don’t change,” Asbell said.
In a retrospective study conducted at the Icahn School of Medicine at Mt. Sinai, Asbell and colleagues found that while the condition of most keratoconus patients remained stable for 3 years, average keratometry readings increased by 2 D or more in 15% of patients. This was before cross-linking was available, Asbell said.
“What we discovered is that most patients over a 3-year follow-up did not change significantly,” she said. “Change in this specific study was defined as the objective metric of average keratometry as determined by topography showing 2 D or more of increased steepening.”
The Collaborative Longitudinal Evaluation of Keratoconus (CLEK) study, which included 1,988 eyes with keratoconus followed over 8 years, showed that corneal steepening as measured by flat manual keratometry increased 3 D or more in about 24% of eyes.
“This result is not that different from what we determined in our study,” Asbell said.
The CLEK study found that best corrected visual acuity decreased by 10 letters or more in 31% of eyes, Asbell said.
“You do have to remember that, for vision, it is a subjective test,” she said. “It depends on the individual reading a chart and therefore open to significant variability.”
There are no standardized definitions of progression in the cross-linking literature, Asbell said. Definitions run the gamut from change in BCVA and change in refractive astigmatism to change in keratometry.
“The question is, how much is truly significant and over what period of time would it be appropriate to determine this change? Is it 2 months, 3 months, 6 months or a year? Neither issue has been well clarified,” Asbell said.
Three cross-linking trials
In her presentation, Asbell reviewed three published randomized, controlled, prospective clinical trials on cross-linking. The main criteria for progression in the trial by Wittig-Silva and colleagues were a 0.75 D or greater increase in cone apex keratometry and a 0.7 D or greater deterioration in manifest refraction spherical equivalent. The main criteria in the trial by O’Brart and colleagues were a one line or greater reduction in corrected or uncorrected visual acuity and a 0.75 or greater increase in corneal astigmatism, keratometry or cone apex power. The main criteria in the trial by Hersh and colleagues were a 1 D or greater increase in keratometry max or manifest refractive cylinder and a 0.5 D or greater increase in manifest refraction spherical equivalent.
Asbell noted that in all three studies, corneal steepening decreased in treated eyes and increased in untreated control eyes. However, steepening increased up to 1.75 D in control eyes in the Wittig-Silva study and less than 0.25 D in controls in the O’Brart and Hersh studies, she said.
LogMAR BCVA decreased up to 0.15 in treated eyes in all three studies. It increased in control eyes in the Wittig-Silva study but decreased in the O’Brart and Hersh studies.
Asbell said there is wide variability of inclusion criteria, definitions of progression and endpoints used in cross-linking trials. Everybody with “progression” was included in the trials, but progression was defined differently for each subject, for example, by a change in glasses prescription for some subjects and for others a steepening of keratometry readings.
“It was a ‘mixed bag’ of patients because they did not all have the same entry criteria,” she said. “We should have better metrics for defining progression or stability, understand the natural history of keratoconus and then do randomized clinical trials.” – by Matt Hasson
- References:
- Hersh PS, et al. J Cataract Refract Surg. 2011;doi:10.1016/j.jcrs.2010.07.030.
- O’Brart DP, et al. Br J Ophthalmol. 2011;doi:10.1136/bjo.2010.196493.
- Wittig-Silva C, et al. Ophthalmology. 2014;doi:10.1016/j.ophtha.2013.10.028.
- For more information:
- Penny A. Asbell, MD, FACS, MBA, can be reached at Mount Sinai School of Medicine, One Gustave L. Levy Place, Box 118, New York, NY 10029; email: penny.asbell@mssm.edu.
Disclosure: Asbell reports no relevant financial disclosures.