Treatment of symptomatic diabetic peripheral neuropathy with the protein kinase C β-inhibitor ruboxistaurin mesylate during a 1-year, randomized, placebo-controlled, double-blind clinical trial

Objective: The aim of this study was to assess the effects of ruboxistaurin (RBX) mesylate on nerve function and sensory symptoms in patients with diabetes mellitus (DM) and diabetic peripheral neuropathy (DPN). Methods: Patients were enrolled in a multinational, randomized, Phase II, double-blind, placebo-controlled parallel-group trial comparing 32 mg/d or 64 mg/d RBX with placebo for 1 year. DPN was identified by abnormal measurable vibration detection threshold (VDT) and verified by abnormal neurologic examination and nerve electrophysiology measures. Baseline patient characteristics (eg, sex, type of DM, age, body mass index, glycosylated hemoglobin, and duration of DM and DPN) were measured. The primary end point was the change in VDT. Secondary end point measures included effects of RBX versus placebo on Neuropathy Total Symptom Score-6 (NTSS-6), neurologic examination, electrophysiologic nerve conduction studies, Neuropathy Impairment Score, Clinical Global Impressions, and safety. A post-hoc analysis was performed on patients with less severe DPN (sural sensory nerve action potential ≥0.5 μV and NTSS-6 total score >6). Results: Two hundred five patients were assessed: 66 were assigned to the RBX 32 mg/d group, 71 to the RBX 64 mg/d group, and 68 to the placebo group. The demographic and baseline characteristics of the treatment groups were well matched between the RBX 32 mg/d, RBX 64 mg/d, and placebo groups: mean (SD) age, 45.6 (8.41) years; 122 (60%) men, 83 (40%) women; 110 (54%) with type 1 DM, 95 (46%) with type 2 DM; mean (SD) duration of DPN, 3.4 (4.21) years. The RBX 32 mg/d group had slightly more patients with type 1 DM (P = 0.05). Eighty-three patients had clinically significant symptoms at baseline (defined as NTSS-6 total score >6: RBX 32 mg/d, n = 22; RBX 64 mg/d, n = 26; placebo, n = 35); 122 patients had NTSS-6 total scores ≤6. No treatment differences were observed for change in VDT. Among the 83 patients with significant symptoms at baseline, there was a reduction from baseline at 12 months in the NTSS-6 total score in the RBX 32 mg/d (P = NS) and RBX 64 mg/d (P = 0.015) groups compared with placebo. In a subgroup of patients with clinically significant symptoms and less severe DPN (n = 50), there was a significantly greater reduction in the NTSS-6 total score with RBX 64 mg/d (P = 0.006 vs placebo). Furthermore, in these patients, there was a statistically significant improvement in VDT for both RBX 32 mg/d (P = 0.012) and RBX 64 mg/d (P = 0.026) compared with placebo. Conclusions: RBX appeared to be well tolerated in the patients with DPN who participated in this study. Overall, changes in VDT and NTSS-6 total scores did not differ among treatment groups at end point. However, RBX treatment appeared to be of benefit for the subgroup of patients with less severe symptomatic DPN by relieving sensory symptoms and improving nerve fiber function, as indicated by reductions in VDT and NTSS-6 total score.