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George W Ousler, Michael Watson, Garrick Wallstrom; Hyper-response to the CAE Challenge Model for Patient Enrichment in Dry Eye Clinical Trials. Invest. Ophthalmol. Vis. Sci. 2019;60(9):2755.
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Selecting the appropriate patient population in clinical trials is critical to demonstrate efficacy of an investigational therapy. The trial participants must have sufficient signs and symptoms of dry eye that are not only consistent over time but also modifiable when treated with a test article. We hypothesized that the rapidity of onset and severity of ocular discomfort in an adverse environmental challenge is predictive of a group that are more sensitive to a drug effect and less prone to a false positive to placebo. A recent clinical trial was selected to explore this possibility.
The trial was a 150-patient phase 2 randomized, prospective, double-masked, study that employed the controlled adverse environment challenge (CAE®) model for screening and efficacy evaluations. Following a two week placebo run-in, patients were randomized to receive either 0.10% HL036, 0.25% HL036 (a Topical TNF-α Inhibitor) or placebo twice daily, with 5 subsequent visits over an 8 week trial duration. A key inclusion criterion required trial participants to demonstrate a worsening in ocular discomfort as defined by a 3 or greater on the 0-4 Ora Calibra® Ocular Discomfort scale during a 90-minute CAE exposure at baseline. An analysis was performed on patients who met this criterion in < 20 min. (considered a more symptomatic patient or hyper-responder) versus ≥ 20 min. to evaluate the impact of CAE response on a daily diary symptom score over the 8 week treatment period.
Patients who had a rapid response to the CAE showed statistically significant differences (p < 0.05) between 0.25% HL036 and placebo for all six weekly symptom score averages beginning with week 3 (Day 15–21). Five of the six weekly averages were statistically significant for 0.10% HL036. Further, in placebo patients changes from baseline were not statistically significant for any week of study, indicating a lack of placebo effect in this subgroup. In patients with a slower response to the CAE no statistically significant differences were found between active groups and placebo for any week.
This study showed both enhanced treatment differences versus placebo in patients with a rapid response to the CAE as well as the lack of a significant placebo effect in such patients. A hyper-response to the CAE challenge model as an inclusion criterion may result in patient enrichment in dry eye clinical trials.
This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.
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