Longer Treatment Duration With Ruboxistaurin (RBX) Is Associated With Less Visual Acuity Decline Over a 6-Year Period Despite Cessation and Reinstitution of Therapy - Results of an Open-Label Extension of the Protein Kinase C-Diabetic Retinopathy Study 2 (PKC-DRS2)

Abstract

Purpose: : The PKC-DRS2 was a phase 3, randomized, double-masked, placebo (PBO)-controlled, 3-year study of the effect of 32 mg/d of RBX on vision loss in patients with moderate to severe nonproliferative diabetic retinopathy (NPDR). RBX reduced the occurrence of sustained moderate visual loss (SMVL, ≥15-letter decline in visual acuity [VA] sustained for the last 6 months of study participation) from 9.1% in the PBO group (N=340) to 5.5% in the RBX group (N=345, p=0.034). This study evaluated the primary endpoint of SMVL in an open-label extension (OLE) study which began a median of 466 days (range 263 to 1296 days) after discontinuation of treatment at the end of PKC-DRS2.

Methods: : Of the 514 patients who completed PKC-DRS2, 203 (39%) enrolled in the OLE for treatment with 32 mg/d RBX for 2 years. Of the 203 enrolled in the OLE, 100 (49%) had previously been treated with PBO (prior PBO subgroup) and 103 had been treated with RBX (prior RBX subgroup).

Results: : PKC-DRS2 baseline patient and ocular characteristics were well-matched between these two subgroups. Using the PKC-DRS2 baseline as the starting point, SMVL occurred in 6% of the prior PBO subgroup during the PKC-DRS2, increasing to 26% by the end of the OLE. In contrast, for the prior RBX subgroup, SMVL occurred in 4% and 8%, respectively (p<0.05 for difference at end of OLE). In the prior PBO subgroup, mean VA declined from 79.6 letters at PKC-DRS2 baseline to 73.1 letters at OLE endpoint (-6.5 letters). The prior RBX subgroup only experienced a 2.7 letter loss (79.8 to 77.1) over the same period (p=0.02). The rate of vision loss in the prior RBX subgroup appeared to accelerate over the drug-free interval, stabilizing after reinstitution of RBX.

Conclusions: : Over a 6-year study period, less SMVL from PKC-DRS2 baseline to end of OLE occurred in the patients with more RBX exposure (~5 years for the prior RBX subgroup versus 2 years for the prior PBO subgroup), even though a ~1-year period of discontinuation in treatment occurred in the prior RBX subgroup.

Clinical Trial: : www.clinicaltrials.gov NCT00266695

Keywords: diabetic retinopathy • visual acuity • clinical (human) or epidemiologic studies: treatment/prevention assessment/controlled clinical trials