Thymosin beta 4 ophthalmic solution for dry eye: a randomized, placebo-controlled, Phase II clinical trial conducted using the controlled adverse environment (CAE) model
Sosne G, Ousler GW
Clinical Ophthalmology (2015) · n=72
A 72-subject Phase 2 dry-eye RCT of 0.1% thymosin β4 ophthalmic solution: the formal primary endpoints did not separate from placebo, but treated subjects showed a 27% reduction in discomfort during controlled adverse environment exposure and statistically significant improvements in corneal staining — the larger companion to the Sosne 2015 Cornea trial.
This is the larger Phase 2 companion to the Sosne 2015 Cornea severe-dry-eye trial. Sosne and Ousler enrolled 72 dry-eye subjects in a single-centre, prospective, double-masked, placebo-controlled Phase 2 trial randomizing 1:1 to either 0.1% thymosin β4 ophthalmic solution (RGN-259) or placebo for 28 days, with assessments using the controlled adverse environment (CAE) model — the standardized low-humidity, high-airflow chamber developed to reproducibly provoke dry-eye signs and symptoms for trial endpoints.
Primary endpoints were ocular discomfort scores and inferior corneal staining at day 29. Secondary endpoints included central and superior corneal staining, conjunctival staining, conjunctival redness, tear-film break-up time, and daily symptom scores. The trial did not meet its formal primary endpoints — there was no statistically significant separation between the RGN-259 and placebo arms on day-29 inferior corneal staining or ocular discomfort. However, in the secondary CAE-exposure analyses, treatment subjects demonstrated a 27% reduction in ocular discomfort during CAE exposure (P=0.0244) and statistically significant improvements in two of the corneal-staining measures (P=0.0075 and P=0.0210). No adverse events were reported in any subject during the trial.
The authors concluded that the trial showed efficacy for symptom relief under provocation and demonstrated "a large safety window, with no adverse events reported by any subjects."
The trial did not meet its prespecified primary endpoints — this is an important honesty marker that gets lost in the secondary "27% discomfort reduction" headline frequently quoted in the thymosin β4 ophthalmic literature. In a regulatory-grade reading, a Phase 2 trial that misses its primary endpoint is a negative trial, even when secondary analyses suggest activity. The CAE-exposure secondary endpoints are valid but were not the prespecified primary outcome, and the multiple-comparisons burden across the secondary analyses is not stated.
The 72-subject sample size is adequate for a Phase 2 trial but still small for definitive efficacy. The 28-day treatment duration is short relative to the chronic-disease framing of dry eye. Industry sponsorship by RegeneRx Biopharmaceuticals is disclosed; this is the larger and methodologically broader of the two 2015 Sosne Phase 2 dry-eye papers, and should be read alongside the 9-patient severe-dry-eye trial as a paired set rather than two independent confirmations. The Phase 3 dry-eye program that followed (ARISE-1, ARISE-2, ARISE-3) has not produced a successful pivotal readout — a fact that should temper any extrapolation from these Phase 2 signals to confirmed clinical efficacy.
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