Aldose reductase inhibitor ranirestat significantly improves nerve conduction velocity in diabetic polyneuropathy: A randomized double-blind placebo-controlled study in Japan

Abstract

Aims/introduction: Diabetic polyneuropathy is one of the most frequent diabetic complications, and impairs patients' quality of life. We evaluated the efficacy and safety of ranirestat (40 mg/day) in patients with diabetic polyneuropathy.

Materials and methods: This was a multicenter, placebo-controlled, randomized double-blind, parallel-group, phase III study in which 557 patients were randomly assigned to either the ranirestat or placebo group and assessed for 52 weeks. The co-primary end-points were the changes in tibial motor nerve conduction velocity and total modified Toronto Clinical Neuropathy Score as a measure of clinical symptoms.

Results: There was a significant increase in tibial motor nerve conduction velocity in the ranirestat group compared with the placebo group. The difference between groups in the change at last observation was 0.52 m/s (P = 0.021). Increases in nerve conduction velocity in the ranirestat group were found not only in the tibial motor nerves, but also in the median motor nerves, proximal median sensory nerves and distal median sensory nerves. No significant differences in modified Toronto Clinical Neuropathy Score or safety parameters were found between the two groups.

Conclusions: Ranirestat (40 mg/day) was well tolerated and improved nerve conduction velocity. Regarding symptoms and signs, no detectable benefits over the placebo were observed in the ranirestat group during the 52 weeks of treatment.

Keywords: Diabetic polyneuropathy; Nerve conduction velocity; Ranirestat.

Figure 1

Study flow diagram. A total of 555 participants (placebo group 278; ranirestat group 277) started treatment with the investigational drug in the treatment period. The full analysis set consisted of 537 participants (269 and 268, respectively), because two participants with no efficacy data related to the primary end‐points, 15 participants who were ineligible for efficacy assessment and one participant who met both criteria were excluded.

Figure 2

Change from baseline to last observation carried forward (LOCF) for each nerve conduction velocity (m/s; full analysis set). Nerve conduction velocities were increased in all investigated nerves in the ranirestat group. Data shown are least square mean ± standard error change from baseline. P‐values were obtained from an analysis of covariance model with change from baseline to LOCF and the baseline value as a covariate. *P < 0.05; **P < 0.01.

Figure 3

Change from baseline to (LOCF) in total modified Toronto Clinical Neuropathy Score (mTCNS; full analysis set). Ranirestat n = 268; placebo n = 269. There was no significant difference between the groups. Data shown are least square mean ± standard error change from baseline. P‐values were obtained from an analysis of covariance model with change from baseline to LOCF and the baseline value as a covariate.

Figure 4

Change from baseline to last observation carried forward in each amplitude (motor nerve, mV; sensory nerve, μV; full analysis set). The compound muscle and sensory nerve action potential amplitudes were increased in all nerves investigated in the ranirestat group. Data shown are least square mean ± standard error change from baseline. P‐values were obtained from an analysis of covariance model with change from baseline to last observation carried forward and the baseline value as a covariate. *P < 0.05.